Substituted triazole derivatives and uses thereof

ABSTRACT

The present invention relates to novel substituted 1,2,4-triazole derivatives, to processes for the preparation of such compounds, to pharmaceutical compositions containing such compounds, and to the use of such compounds or compositions for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of renal and cardiovascular diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the National Stage entry of InternationalApplication No. PCT/EP2018/078411, filed 17 Oct. 2018, which claimspriority to European Patent Application No. 17197946.1, filed 24 Oct.2017.

BACKGROUND Field

The present invention relates to novel substituted 1,2,4-triazolederivatives, to processes for the preparation of such compounds, topharmaceutical compositions containing such compounds, and to the use ofsuch compounds or compositions for the treatment and/or prevention ofdiseases, in particular for the treatment and/or prevention of renal andcardiovascular diseases.

Description of Related Art

Vasopressin is a neurohormone which basically regulates waterhomeostasis and vascular tone. It is produced in specialized endocrineneurons in the Nucleus supraopticus and N. paraventricularis in the wallof the third ventricle (hypothalamus) and is transported from therealong the neural processes into the posterior lobes of the hypophysis(neurohypophysis). There, the hormone is released into the bloodstreamin response to different physiological and pathophysiological stimuli. Adisturbed neurohormonal regulation essentially manifests itself in anelevation of the sympathetic tone and inappropriate activation of therenin-angiotensin-aldosterone system (RAAS). While the inhibition ofthese components by beta-receptor blockers on the one hand by ACEinhibitors or angiotensin-receptor blockers on the other is now aninherent part of the pharmacological treatment of cardiovasculardiseases, the inappropriate elevation of vasopressin secretion is atpresent still not adequately treatable.

Vasopressin exerts its action mainly via binding to three receptors,which are classified as V1a, V1b and V2 receptors and which belong tothe family of G protein-coupled receptors.

V2 receptors are located in the distal tubular epithelium and theepithelium of the collecting tubules in the kidney. Their activationrenders these epithelia permeable to water. This phenomenon is due tothe incorporation of aquaporins (special water channels) in the luminalmembrane of the epithelial cells. Consequently, pharmacologicalinhibition of the action of vasopressin on the V2 receptor results inincreased urine excretion. Hence, drugs with V2 antagonistic activityappear particularly suitable for the treatment of all disease conditionswhich are associated with an overloading of the body with water.

V1b receptors (also named V3 receptors) are mainly detectable in thecentral nervous system. Together with corticotropin-releasing hormone(CRH), vasopressin regulates the basal and stress-induced secretion ofadrenocorticotropic hormone (ACTH) via the V1b receptor.

V1a receptors are mainly located on vascular smooth muscle cells (VSMC)but also on cardiomyocytes, fibroblasts and specialized renal cells likeglomerular mesangial cells or cells of the macula densa which controlthe release of renin [Wasilewski M A, Myers V D, Recchia F A, Feldman AM, Tilley D G, Cell Signal., 28(3), 224-233, (2016)]. The activation ofVSMC V1a receptor by vasopressin gives rise to intracellular calciumrelease and according vasoconstriction. Therefore, stimulation of VSMCV1a receptors causes increased vascular resistance and increased cardiacafterload. Cardiac output is adversely affected by V1a-mediatedvasoconstriction. The increase in afterload and direct stimulation ofV1a receptors on cardiomyocytes can lead to cardiac hypertrophy andremodeling including fibrosis. Mice with cardiac-specific overexpressionof V1a receptor develop cardiac hypertrophy leading to dilation and leftventricular dysfunction, suggesting an essential role for V1a receptorin the development of heart failure [Li X, Chan T O, Myers V, ChowdhuryI, Zhang X Q, Song J, Zhang J, Andrei J, Funakoshi H, Robbins J, Koch WJ, Hyslop T, Cheung J Y, Feldman A M, Circulation.; 124, 572-581(2011)].

V1a receptor is also expressed in the renal cortical and medullaryvasculature, where it mediates vasoconstriction of renal vessels andaffecting overall renal blood flow. Thus, the activation of V1a receptorcan decrease renal medullary blood flow inducing further pathologicalprocesses as tissue hypoxia, reduced oxygen and accordingly energysupply for tubular transport processes as well as direct damages ofmesangial and macula densa cells. It has been demonstrated thatmesangial V1a receptor activation mediates TGFβ signaling and causes anincrease in production of collagen IV. While this signaling contributesto extracellular matrix accumulation and remodeling in the kidney,similar signaling pathways are believed to occur in cardiac cellsespecially after myocardial infarction, which emphasizes the centralrole of V1a receptor in the development of hypertrophic and fibroticprocesses in response to pathophysiological elevated vasopressin levels[Wasilewski M A, Myers V D, Recchia F A, Feldman A M, Tilley D G.Arginine vasopressin receptor signaling and functional outcomes in heartfailure. Cell Signal., 28(3), 224-233 (2016)].

Since V1a receptors are mainly expressed on VSMCs and thus participatingin vascular function, a link to vascular diseases as peripheral arterialdisease (PAD) including claudication and critical limb ischemia as wellas coronary microvascular dysfunction (CMD) is conceivable.

Apart from this, V1a receptors are also expressed on human platelets andin the liver. The meaning of platelet V1a receptors is not fullyunderstood although vasopressin induces aggregation of human plateletsvia V1a receptor at high concentrations ex vivo. Therefore, inhibitionof vasopressin-induced platelet aggregation by V1a receptor antagonistsis a useful pharmacological ex vivo assay making use of human tissueendogenously expressing the V1a receptor [Thibonnier M, Roberts J M, JClin Invest.; 76:1857-1864, (1985)].

Vasopressin stimulates gluconeogenesis and glycogenolysis via activationof the hepatic V1a receptor. Animal studies have shown that vasopressinimpairs glucose tolerance which could be inhibited by a V1a receptorantagonist thereby providing a link of vasopressin receptor V1a todiabetes mellitus. [Taveau C, Chollet C, Waeckel L, Desposito D, BichetD G, Arthus M F, Magnan C, Philippe E, Paradis V, Foufelle F, HainaultI, Enhorning S, Velho G, Roussel R, Bankir L, Melander O, Bouby N.Vasopressin and hydration play a major role in the development ofglucose intolerance and hepatic steatosis in obese rats. Diabetologia,58(5), 1081-1090, (2015)].

Vasopressin was shown to contribute to the development of albuminuriaand to diabetes-induced nephropathy in animal models which is consistentwith epidemiological findings in humans.

It was found recently that vasopressin also seems to play a causal rolein the development of preeclampsia. Chronic infusion of vasopressinduring pregnancy in mice is sufficient to induce all of the majormaternal and fetal phenotypes associated with human preeclampsia,including pregnancy-specific hypertension [Santillan M K, Santillan D A,Scroggins S M, MM JY, Sandgren J A, Pearson N A, Leslie K K, Hunter S K,Zamba G K, Gibson-Corley K N, Grobe J L. Vasopressin in preeclampsia: anovel very early human pregnancy biomarker and clinically relevant mousemodel. Hypertension. 64(4), 852-859, (2014)].

Vasopressin levels can be elevated in women with dysmenorrhoea (agynecological disorder which is characterised by cyclical crampingpelvic pain) during menstruation, which appear to increase myometrialsmooth muscle contraction. It was found recently that a selectivevasopressin V1a receptor antagonist (relcovaptan/SR-49059) can reduceintrauterine contractions elicited by vasopressin.

For these reasons, agents which inhibit the action of vasopressin on theV1a receptor appear suitable for the treatment of several cardiovasculardiseases. In particular, agents which inhibit the action of vasopressinselectively on the V1a receptor offer an especially ideal profile forthe treatment of otherwise normovolemic patients, i.e. those which arenot eligible for decongestion by e.g. high doses of loop diuretics or V2antagonists, and where induced aquaresis via V2 inhibition may beundesired.

Certain 4-phenyl-1,2,4-triazol-3-yl derivatives have been described inWO 2005/063754-A1 and WO 2005/105779-A1 to act as vasopressin V1areceptor antagonists that are useful for the treatment of gynecologicaldisorders, notably menstrual disorders such as dysmenorrhea.

In WO 2011/104322-A1, a particular group of bis-aryl-bonded1,2,4-triazol-3-ones, including 5 phenyl-1,2,4-triazol-3-yl and1-phenyl-1,2,3-triazol-4-yl derivatives thereof, has been disclosed asantagonists of vasopressin V2 and/or V1a receptors being useful for thetreatment and/or prevention of cardiovascular diseases. The describedcompounds, however, do not show sufficient selectivity towards the V1areceptor and mostly show combined activity on both vasopressin V1a andV2 receptors. Yet, as outlined above, a high affinity as well asselectivity for the V1a receptor is a desirable prerequisite for thetreatment of disease conditions where a decongestion is not desired andmay lead to a dysregulated body fluid homeostasis including decreasedblood plasma osmolality in otherwise normovolemic individuals.

In WO 2016/071212-A1 certain 5-(hydroxyalkyl)-1-phenyl-1,2,4-triazolederivatives have been disclosed, which act as potent antagonists of bothvasopressin V1a and V2 receptors and, in addition, exhibit significantlyenhanced aquaretic potency in vivo after oral application. The compoundsare described to be useful for the treatment and/or prevention ofcardiovascular and renal diseases. Yet, as outlined above, a highaffinity as well as selectivity for the V1a receptor is a desirableprerequisite for the treatment of disease conditions where adecongestion is not desired and may lead to a dysregulated body fluidhomeostasis including decreased blood plasma osmolality in otherwisenormovolemic individuals.

In WO 2017/191107-A1 and WO 2017/191102-A1 certain5-(carboxamide)-1-phenyl-1,2,4-triazole derivatives as well as in WO2017/191114-A1 specific 5-(hydroxyalkyl)-1-heteroaryl-1,2,4-triazolederivatives have been described, which represent highly potent andselective antagonists of the V1a receptor and are particularly usefulfor the treatment and/or prevention of renal and cardiovascular diseasesin subjects which do not suffer from fluid overload and who thereforeshould not be decongested.

Further novel 5-(carboxamide)-substituted, 5-(fluoroalkyl)-substitutedand 3-(hydroxyalkyl)-substituted 1,2,4-triazole derivatives have beendisclosed as antagonists of vasopressin V2 and/or V1a receptors in WO2017/191105-A1, WO 2017/191112-A1, WO 2017/191115-A1 and WO2018/073144-A1.

An activity profile with a high selectivity for the V1a receptor has alow potential to cause unwanted off-target related side effects andwould also help towards reducing the amount of substance which is goingto be required to achieve and maintain the desired therapeutic effect,thus limiting the potential for unacceptable side effects and/orunwanted drug-drug interactions during the treatment of patients whichmight already be at high risk, such as, for example, in acute or chronicheart and kidney diseases.

SUMMARY

The technical problem to be solved according to the present inventionmay therefore be seen in identifying and providing new compounds thatact as potent antagonists of the vasopressin V1a receptor. A furtherobject of the invention is to identify and provide new compounds with ahigh affinity and selectivity vis-à-vis the vasopressin V1a receptor.The compounds are intended to avoid inducing aquaresis via V2inhibition. The compounds are further intended to have a similar orimproved therapeutic profile compared to the compounds known from theprior art, for example with respect to their in vivo properties, forexample their pharmacokinetic and pharmacodynamic characteristics and/ortheir metabolic profile and/or their dose-activity relationship.

Surprisingly, it has now been found that certain substituted1,2,4-triazole derivatives represent highly potent and selectiveantagonists of the V1a receptor. This specific profile renders thecompounds of the present invention useful for the treatment and/orprevention of diseases, which are associated with V1a receptoractivation. The compounds of the present invention are particularlyuseful for the treatment and/or prevention of renal and cardiovasculardiseases in subjects which do not suffer from fluid overload and whotherefore should not be decongested.

The compounds of the present invention have valuable pharmacologicalproperties and can be used for the prevention and/or treatment ofvarious diseases and disease-induced states in humans and other mammals.

The invention provides compounds of the general formula (I)

in which

-   R¹ represents C₁-C₄-alkyl, 3,3,3-trifluoro-prop-1-en-1-yl,    2,3,3-trifluoro-prop-2-en-1-yl, cyclopropyl, cyclobutyl,    oxetan-2-yl, oxetan-3-yl, azetidin-2-yl, pyrrolidin-2-yl,    pyrrolidin-3-yl, 1,1-dioxo-thietan-3-yl,    1,1-dioxo-tetrahydrothiophen-3-yl, 5-chloro-thiophen-2-yl or    2-oxoimidazolidin-4-yl,    -   where alkyl may be substituted by 1 or 2 substituents        independently of one another selected from the group consisting        of cyano, fluorine, hydroxy, trifluoromethyl, methoxy,        methylsulfonyl, methylcarbonyloxy, methylsulfonylamino and        2-oxo-1,3-oxazolidin-3-yl,    -   and    -   where cyclopropyl and cyclobutyl may be substituted by 1 or 2        substituents independently of one another selected from the        group consisting of cyano, fluorine, hydroxy, amino,        trifluoromethyl and tert-butoxycarbonylamino,    -   and    -   where azetidin-2-yl may be substituted by 1 to 3 substituents        independently of one another selected from the group consisting        of fluorine and tert-butoxycarbonyl, and    -   where pyrrolidin-2-yl and pyrrolidin-3-yl may be substituted by        1 or 2 substituents independently of one another selected from        the group consisting of oxo, fluorine, trifluoromethyl and        tert-butoxycarbonyl,-   R² represents chlorine, trifluoromethyl or trifluoromethoxy,

and pharmaceutically acceptable salts thereof, solvates thereof and thesolvates of the salts thereof.

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT

The term “substituted” means that one or more hydrogen atoms on thedesignated atom or group are replaced with a selection from theindicated group, provided that the designated atom's normal valencyunder the existing circumstances is not exceeded. Combinations ofsubstituents and/or variables are permissible.

The term “optionally substituted” means that the number of substituentscan be equal to or different from zero. Unless otherwise indicated, itis possible that optionally substituted groups are substituted with asmany optional substituents as can be accommodated by replacing ahydrogen atom with a non-hydrogen substituent on any available carbonatom or heteroatom.

When groups in the compounds according to the invention are substituted,it is possible for said groups to be mono-substituted orpoly-substituted with substituent(s), unless otherwise specified. Withinthe scope of the present invention, the meanings of all groups whichoccur repeatedly are independent from one another. It is possible thatgroups in the compounds according to the invention are substituted withone, two or three identical or different substituents.

The term “comprising” when used in the specification includes“consisting of”.

If within the present text any item is referred to as “as mentionedherein”, it means that it may be mentioned anywhere in the present text.

The terms as mentioned in the present text have the following meanings:

C₁-C₄-Alkyl represents a straight-chain or branched alkyl radical having1 to 4 carbon atoms, preferably 1 to 3 carbon atoms (C₁-C₃-alkyl), byway of example and with preference methyl, ethyl, n-propyl, isopropyl,2-methylprop-1-yl, n-butyl and tert-butyl.

It is possible for the compounds of general formula (I) to exist asisotopic variants. The invention therefore includes one or more isotopicvariant(s) of the compounds of general formula (I), particularlydeuterium-containing compounds of general formula (I).

The term “Isotopic variant” of a compound or a reagent is defined as acompound exhibiting an unnatural proportion of one or more of theisotopes that constitute such a compound.

The term “Isotopic variant of the compound of general formula (I)” isdefined as a compound of general formula (I) exhibiting an unnaturalproportion of one or more of the isotopes that constitute such acompound.

The expression “unnatural proportion” means a proportion of such isotopewhich is higher than its natural abundance. The natural abundances ofisotopes to be applied in this context are described in “IsotopicCompositions of the Elements 1997”, Pure Appl. Chem., 70(1), 217-235,1998.

Examples of such isotopes include stable and radioactive isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine,chlorine, bromine and iodine, such as ²H (deuterium), ³H (tritium), ¹¹C,¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²F, ³³F, ³³ s, ³⁴ s, ³⁵ s, ³⁶ s, ¹⁸F, ³⁶Cl,⁸²Br, ¹²³I, ¹²⁴I, ¹²⁵I, ¹²⁹I and ¹³¹I, respectively.

With respect to the treatment and/or prevention of the disordersspecified herein the isotopic variant(s) of the compounds of generalformula (I) preferably contain deuterium (“deuterium-containingcompounds of general formula (I)”). Isotopic variants of the compoundsof general formula (I) in which one or more radioactive isotopes, suchas ³H or ¹⁴C, are incorporated are useful e.g. in drug and/or substratetissue distribution studies. These isotopes are particularly preferredfor the ease of their incorporation and detectability. Positron emittingisotopes such as ¹⁸F or ¹¹C may be incorporated into a compound ofgeneral formula (I). These isotopic variants of the compounds of generalformula (I) are useful for in vivo imaging applications.Deuterium-containing and ¹³C-containing compounds of general formula (I)can be used in mass spectrometry analyses (H. J. Leis et al., Curr. Org.Chem., 1998, 2, 131) in the context of preclinical or clinical studies.

Isotopic variants of the compounds of general formula (I) can generallybe prepared by methods known to a person skilled in the art, such asthose described in the schemes and/or examples herein, by substituting areagent for an isotopic variant of said reagent, preferably for adeuterium-containing reagent. Depending on the desired sites ofdeuteration, in some cases deuterium from D₂O can be incorporated eitherdirectly into the compounds or into reagents that are useful forsynthesizing such compounds (Esaki et al., Tetrahedron, 2006, 62, 10954;Esaki et al., Chem. Eur. J., 2007, 13, 4052). Deuterium gas is also auseful reagent for incorporating deuterium into molecules. Catalyticdeuteration of olefinic bonds (H. J. Leis et al., Curr. Org. Chem.,1998, 2, 131; J. R. Morandi et al., J. Org. Chem., 1969, 34 (6), 1889)and acetylenic bonds (N. H. Khan, J. Am. Chem. Soc., 1952, 74 (12),3018; S. Chandrasekhar et al., Tetrahedron Letters, 2011, 52, 3865) is adirect route for incorporation of deuterium. Metal catalysts (i.e. Pd,Pt, and Rh) in the presence of deuterium gas can be used to directlyexchange deuterium for hydrogen in functional groups containinghydrocarbons (J. G. Atkinson et al., U.S. Pat. No. 3,966,781). A varietyof deuterated reagents and synthetic building blocks are commerciallyavailable from companies such as for example C/D/N Isotopes, Quebec,Canada; Cambridge Isotope Laboratories Inc., Andover, Mass., USA; andCombiPhos Catalysts, Inc., Princeton, N.J., USA. Further information onthe state of the art with respect to deuterium-hydrogen exchange isgiven for example in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990;R. P. Hanzlik et al., Biochem. Biophys. Res. Commun. 160, 844, 1989; P.J. Reider et al., J. Org. Chem. 52, 3326-3334, 1987; M. Jarman et al.,Carcinogenesis 16(4), 683-688, 1995; J. Atzrodt et al., Angew. Chem.,Int. Ed. 2007, 46, 7744; K. Matoishi et al., Chem. Commun. 2000,1519-1520; K. Kassahun et al., WO2012/112363.

The term “deuterium-containing compound of general formula (I)” isdefined as a compound of general formula (I), in which one or morehydrogen atom(s) is/are replaced by one or more deuterium atom(s) and inwhich the abundance of deuterium at each deuterated position of thecompound of general formula (I) is higher than the natural abundance ofdeuterium, which is about 0.015%. Particularly, in adeuterium-containing compound of general formula (I) the abundance ofdeuterium at each deuterated position of the compound of general formula(I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferablyhigher than 90%, 95%, 96% or 97%, even more preferably higher than 98%or 99% at said position(s). It is understood that the abundance ofdeuterium at each deuterated position is independent of the abundance ofdeuterium at other deuterated position(s).

The selective incorporation of one or more deuterium atom(s) into acompound of general formula (I) may alter the physicochemical properties(such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc.,2007, 129, 4490; A. Streitwieser et al., J. Am. Chem. Soc., 1963, 85,2759;], basicity [C. L. Perrin et al., J. Am. Chem. Soc., 2005, 127,9641; C. L. Perrin, et al., J. Am. Chem. Soc., 2003, 125, 15008; C. L.Perrin in Advances in Physical Organic Chemistry, 44, 144],lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3), 271])and/or the metabolic profile of the molecule and may result in changesin the ratio of parent compound to metabolites or in the amounts ofmetabolites formed. Such changes may result in certain therapeuticadvantages and hence may be preferred in some circumstances. Reducedrates of metabolism and metabolic switching, where the ratio ofmetabolites is changed, have been reported (A. E. Mutlib et al.,Toxicol. Appl. Pharmacol., 2000, 169, 102; D. J. Kushner et al., Can. J.Physiol. Pharmacol., 1999, 77, 79). These changes in the exposure toparent drug and metabolites can have important consequences with respectto the pharmacodynamics, tolerability and efficacy of adeuterium-containing compound of general formula (I). In some casesdeuterium substitution reduces or eliminates the formation of anundesired or toxic metabolite and enhances the formation of a desiredmetabolite (e.g. Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol.,2013, 26, 410; Efavirenz: A. E. Mutlib et al., Toxicol. Appl.Pharmacol., 2000, 169, 102). In other cases the major effect ofdeuteration is to reduce the rate of systemic clearance. As a result,the biological half-life of the compound is increased. The potentialclinical benefits would include the ability to maintain similar systemicexposure with decreased peak levels and increased trough levels. Thiscould result in lower side effects and enhanced efficacy, depending onthe particular compound's pharmacokinetic/pharmacodynamic relationship.ML-337 (C. J. Wenthur et al., J. Med. Chem., 2013, 56, 5208) andOdanacatib (K. Kassahun et al., WO2012/112363) are examples for thisdeuterium effect. Still other cases have been reported in which reducedrates of metabolism result in an increase in exposure of the drugwithout changing the rate of systemic clearance (e.g. Rofecoxib: F.Schneider et al., Arzneim. Forsch./Drug. Res., 2006, 56, 295;Telaprevir: F. Maltais et al., J. Med. Chem., 2009, 52, 7993).Deuterated drugs showing this effect may have reduced dosingrequirements (e.g. lower number of doses or lower dosage to achieve thedesired effect) and/or may produce lower metabolite loads.

A compound of general formula (I) may have multiple potential sites ofattack for metabolism. To optimize the above-described effects onphysicochemical properties and metabolic profile, deuterium-containingcompounds of general formula (I) having a certain pattern of one or moredeuterium-hydrogen exchange(s) can be selected. Particularly, thedeuterium atom(s) of deuterium-containing compound(s) of general formula(I) is/are attached to a carbon atom and/or is/are located at thosepositions of the compound of general formula (I), which are sites ofattack for metabolizing enzymes such as e.g. cytochrome P₄₅₀.

Where the plural form of the word compounds, salts, polymorphs,hydrates, solvates and the like, is used herein, this is taken to meanalso a single compound, salt, polymorph, isomer, hydrate, solvate or thelike.

By “stable compound′ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The compounds of the present invention optionally contain one asymmetriccentre, depending upon the location and nature of the varioussubstituents desired. It is possible that one asymmetric carbon atom ispresent in the (R) or (S) configuration, which can result in racemicmixtures. In certain instances, it is possible that asymmetry also bepresent due to restricted rotation about a given bond, for example, thecentral bond adjoining two substituted aromatic rings of the specifiedcompounds. Preferred compounds are those which produce the moredesirable biological activity. Separated, pure or partially purifiedisomers and stereoisomers or racemic mixtures of the compounds of thepresent invention are also included within the scope of the presentinvention. The purification and the separation of such materials can beaccomplished by standard techniques known in the art.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereoisomeric salts using an optically active acid orbase or formation of covalent diastereomers. Examples of appropriateacids are tartaric, diacetyltartaric, ditoluoyltartaric andcamphorsulfonic acid. Mixtures of diastereoisomers can be separated intotheir individual diastereomers on the basis of their physical and/orchemical differences by methods known in the art, for example, bychromatography or fractional crystallisation. The optically active basesor acids are then liberated from the separated diastereomeric salts. Adifferent process for separation of optical isomers involves the use ofchiral chromatography (e.g., HPLC columns using a chiral phase), with orwithout conventional derivatisation, optimally chosen to maximise theseparation of the enantiomers. Suitable HPLC columns using a chiralphase are commercially available, such as those manufactured by Daicel,e.g., Chiracel O D and Chiracel O J, for example, among many others,which are all routinely selectable. Enzymatic separations, with orwithout derivatisation, are also useful. The optically active compoundsof the present invention can likewise be obtained by chiral synthesesutilizing optically active starting materials. In order to distinguishdifferent types of isomers from each other reference is made to IUPACRules Section E (Pure Appl Chem 45, 11-30, 1976).

The present invention includes all possible stereoisomers of thecompounds of the present invention as single stereoisomers, or as anymixture of said stereoisomers, e.g. (R)- or (S)-isomers, in any ratio.Isolation of a single stereoisomer, e.g. a single enantiomer or a singlediastereomer, of a compound of the present invention is achieved by anysuitable state of the art method, such as chromatography, especiallychiral chromatography, for example.

In the context of the present invention, the term “enantiomericallypure” is to be understood as meaning that the compound in question withrespect to the absolute configuration of the chiral centre is present inan enantiomeric excess of more than 95%, preferably more than 97%. Theenantiomeric excess, ee, is calculated here by evaluating of thecorresponding HPLC chromatogram on a chiral phase using the formulabelow:ee=[E ^(A)(area %)−E ^(B)(area %)]×100%/[E ^(A)(area %)+E ^(B)(area %)]

(E^(A): major enantiomer, E^(B): minor enantiomer)

Further, it is possible for the compounds of the present invention toexist as tautomers. The present invention includes all possibletautomers of the compounds of the present invention as single tautomers,or as any mixture of said tautomers, in any ratio.

Further, the compounds of the present invention can exist as N-oxides,which are defined in that at least one nitrogen of the compounds of thepresent invention is oxidised. The present invention includes all suchpossible N-oxides.

The present invention also covers useful forms of the compounds of thepresent invention, such as metabolites, hydrates, solvates, salts, inparticular pharmaceutically acceptable salts, and/or co-precipitates.

The compounds of the present invention can exist as a hydrate, or as asolvate, wherein the compounds of the present invention contain polarsolvents, in particular water, methanol or ethanol for example, asstructural element of the crystal lattice of the compounds. It ispossible for the amount of polar solvents, in particular water, to existin a stoichiometric or non-stoichiometric ratio. In the case ofstoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-,di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, arepossible. The present invention includes all such hydrates or solvates.Hydrates are preferred solvates in the context of the present invention.

Further, it is possible for the compounds of the present invention toexist in free form, e.g. as a free base, or as a free acid, or as azwitterion, or to exist in the form of a salt. Said salt may be anysalt, either an organic or inorganic addition salt, particularly anypharmaceutically acceptable organic or inorganic addition salt, which iscustomarily used in pharmacy, or which is used, for example, forisolating or purifying the compounds of the present invention.

The term “pharmaceutically acceptable salt” refers to an inorganic ororganic acid addition salt of a compound of the present invention. Forexample, see S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci.1977, 66, 1-19.

A suitable pharmaceutically acceptable salt of the compounds of thepresent invention may be, for example, an acid-addition salt of acompound of the present invention bearing a nitrogen atom, in a chain orin a ring, for example, which is sufficiently basic, such as anacid-addition salt with an inorganic acid, or “mineral acid”, such ashydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric,phosphoric, or nitric acid, for example, or with an organic acid, suchas formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic,butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic,2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic,cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic,pamoic, pectinic, 3-phenylpropionic, pivalic, 2-hydroxyethanesulfonic,itaconic, trifluoromethanesulfonic, dodecylsulfuric, ethanesulfonic,benzenesulfonic, para-toluenesulfonic, methanesulfonic,2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid,citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic,adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic,glucoheptanoic, glycerophosphoric, aspartic, sulfosalicylic, orthiocyanic acid, for example.

Further, another suitably pharmaceutically acceptable salt of a compoundof the present invention which is sufficiently acidic, is an alkalimetal salt, for example a sodium or potassium salt, an alkaline earthmetal salt, for example a calcium, magnesium or strontium salt, or analuminium or a zinc salt, or an ammonium salt derived from ammonia orfrom an organic primary, secondary or tertiary amine having 1 to 20carbon atoms, such as ethylamine, diethylamine, triethylamine,ethyldiisopropylamine, monoethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, dimethylaminoethanol,diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine,dibenzylamine, N-methylmorpholine, arginine, lysine,1,2-ethylenediamine, N-methylpiperidine, N-methyl-glucamine,N,N-dimethyl-glucamine, N-ethyl-glucamine, 1,6-hexanediamine,glucosamine, sarcosine, serinol, 2-amino-1,3-propanediol,3-amino-1,2-propanediol, 4-amino-1,2,3-butanetriol, or a salt with aquarternary ammonium ion having 1 to 20 carbon atoms, such astetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium,tetra(n-butyl) ammonium, N-benzyl-N,N,N-trimethylammonium, choline orbenzalkonium.

Those skilled in the art will further recognise that it is possible foracid addition salts of the claimed compounds to be prepared by reactionof the compounds with the appropriate inorganic or organic acid via anyof a number of known methods. Alternatively, alkali and alkaline earthmetal salts of acidic compounds of the present invention are prepared byreacting the compounds of the present invention with the appropriatebase via a variety of known methods.

The present invention includes all possible salts of the compounds ofthe present invention as single salts, or as any mixture of said salts,in any ratio.

In the present text, in particular in the Experimental Section, for thesynthesis of intermediates and of examples of the present invention,when a compound is mentioned as a salt form with the corresponding baseor acid, the exact stoichiometric composition of said salt form, asobtained by the respective preparation and/or purification process, is,in most cases, unknown.

Unless specified otherwise, suffixes to chemical names or structuralformulae relating to salts, such as “hydrochloride”, “trifluoroacetate”,“sodium salt”, or “x HCl”, “x CF₃COOH”, “x Na⁺”, for example, mean asalt form, the stoichiometry of which salt form not being specified.

This applies analogously to cases in which synthesis intermediates orexample compounds or salts thereof have been obtained, by thepreparation and/or purification processes described, as solvates, suchas hydrates, with (if defined) unknown stoichiometric composition.

Furthermore, the present invention includes all possible crystallineforms, or polymorphs, of the compounds of the present invention, eitheras single polymorph, or as a mixture of more than one polymorph, in anyratio.

Furthermore, the present invention also embraces prodrugs of thecompounds of the invention. The term “prodrugs” denotes compounds whichmay themselves be biologically active or inactive but which during theirresidence time in the body are converted (metabolically or byhydrolysis, for example) into compounds of the invention.

Preference is given to compounds of the general formula (I) in which

-   R¹ represents methyl, ethyl, 3,3,3-trifluoro-prop-1-en-1-yl,    1-trifluoromethylcycloprop-1-yl, 2,2-difluorocycloprop-1-yl,    4-fluoropyrrolidin-2-yl, 5-oxopyrrolidin-2-yl,    1,1-dioxo-thietan-3-yl or 5-chloro-thiophen-2-yl,    -   where methyl is substituted by one substituent selected from the        group consisting of trifluoromethyl, methoxy and methylsulfonyl,    -   and    -   where ethyl is substituted by one substituent trifluoromethyl,-   R² represents chlorine or trifluoromethyl,

and pharmaceutically acceptable salts thereof, solvates thereof and thesolvates of the salts thereof.

Preference is also given to compounds of the general formula (I) inwhich

-   R¹ represents methyl, ethyl, 2,2-difluorocycloprop-1-yl,    4-fluoropyrrolidin-2-yl or 5-oxopyrrolidin-2-yl,    -   where methyl is substituted by one substituent methylsulfonyl,    -   and    -   where ethyl is substituted by one substituent trifluoromethyl,-   R² represents chlorine,

and pharmaceutically acceptable salts thereof, solvates thereof and thesolvates of the salts thereof.

Preference is also given to compounds of the general formula (I) inwhich R² represents chlorine.

In a particular further embodiment of the first aspect, the presentinvention covers combinations of two or more of the above mentionedembodiments under the heading “further embodiments of the first aspectof the present invention”.

The present invention covers any sub-combination within any embodimentor aspect of the present invention of compounds of general formula (I).

The present invention covers the compounds of general formula (I) whichare disclosed in the Example Section of this text, infra.

The invention further provides a process for preparing the compounds ofthe general formula (I), or the pharmaceutically acceptable saltsthereof, solvates thereof or the solvates of the salts thereof, whereinthe compounds of the formula

in which

R² has the meaning as defined for the compounds of general formula (I)given above, are reacted with compounds of the formula

in which

X¹ represents chlorine or hydroxy, and

R¹ has the meaning as defined for the compounds of general formula (I)given above, to give compounds of the general formula (I),

optionally followed, where appropriate, by (i) separating the compoundsof the general formula (I) thus obtained into their respectivediastereomers, and/or (ii) converting the compounds of the generalformula (I) into their respective pharmaceutically acceptable saltsthereof, solvates thereof or the solvates of the salts thereof bytreatment with the corresponding solvents and/or acids or bases.

The present invention covers methods of preparing compounds of thepresent invention of general formula (I), said methods comprising thesteps as described in the Experimental Section herein.

The schemes and procedures described below illustrate synthetic routesto the compounds of general formula (I) of the invention and are notintended to be limiting. In addition, interconversion of the substituentR¹ can be achieved before and/or after the exemplified transformations.These modifications can be such as the introduction of protectinggroups, cleavage of protecting groups, reduction or oxidation offunctional groups, halogenation, metallation, substitution or otherreactions known to the person skilled in the art. These transformationsinclude those which introduce a functionality which allows for furtherinterconversion of substituents. Appropriate protecting groups and theirintroduction and cleavage are well-known to the person skilled in theart (see for example T.W. Greene and P.G.M. Wuts in Protective Groups inOrganic Synthesis, 3rd edition, Wiley 1999). Specific examples aredescribed in the subsequent paragraphs.

The reaction, if X¹ represents chlorine, is generally carried out byreacting a compound of the formula (II) with a compound of the formula(III) in an inert solvent in the presence of a base, preferably in atemperature range from 0° C. to +100° C., more preferably at 0° C. to+40° C. The reactions can be carried out at atmospheric, at elevated orat reduced pressure (for example at from 0.5 to 5 bar); in general, thereactions are carried out at atmospheric pressure.

Inert solvents for the process step (II)+(III)→(I), if X¹ representschlorine, are, for example, halogenated hydrocarbons such asdichloromethane or trichloromethane, hydrocarbons such as benzene, orother solvents such as nitromethane, dioxane, dimethylformamide,dimethyl sulphoxide or acetonitrile. It is also possible to use mixturesof the solvents. Preference is given to dichloromethane.

Suitable bases for process step (II)+(III)→(I), if X¹ representschlorine, are, for example, alkali metal carbonates such as sodiumcarbonate or potassium carbonate, or sodium bicarbonate or potassiumbicarbonate, or organic bases such as trialkylamines, for exampletriethylamine, N-methylmorpholine, N-methylpiperidine,4-dimethylaminopyridine or diisopropylethylamine. The condensation ispreferably carried out using diisopropylethylamine.

The reaction, if X¹ represents hydroxyl, is generally carried out byreacting a compound of the formula (II) with a compound of the formula(III) in an inert solvent with the help of a condensing agent oractivating agent in the presence of a base, preferably in a temperaturerange from 0° C. to +100° C., more preferably at 0° C. to +40° C. Thereactions can be carried out at atmospheric, at elevated or at reducedpressure (for example at from 0.5 to 5 bar); in general, the reactionsare carried out at atmospheric pressure.

Inert solvents for the process step (II)+(III)→(I), if X¹ representshydroxyl, are, for example, halogenated hydrocarbons such asdichloromethane or trichloromethane, hydrocarbons such as benzene, orother solvents such as nitromethane, dioxane, dimethylformamide,dimethyl sulphoxide or acetonitrile. It is also possible to use mixturesof the solvents. Preference is given to dimethylformamide.

Condensation and activating agents for process step (II)+(III)→(I), ifX¹ represents hydroxyl, are, for example, carbodiimides such asN,N′-diethyl-, N,N′-dipropyl-,N,N′-diisopropyl-N,N′-dicyclohexyl-carbodiimide (DCC) orN-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC),phosgene derivatives such as N, N′-carbonyldiimidazole (CDI),1,2-oxazolium compounds such as2-ethyl-5-phenyl-1,2-oxazolium-3-sulphate or2-tert-butyl-5-methyl-isoxazolium perchlorate, acylamino compounds suchas 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or isobutylchloroformate, propanephosphonic anhydride, diethyl cyano-phosphonate,bis(2-oxo-3-oxazo-lidinyl)phosphoryl chloride,benzotriazol-1-yloxytris(dimethyl-amino)phosphonium hexafluorophosphate,benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate(PyBOP), O-(benzotriazol-1-yl)-N, N, N′,N′-tetramethyluroniumtetrafluoroborate (TBTU),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TPTU),O-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate(HATU) or O-(1H-6-chloro-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TCTU), optionally in combination with other additivessuch as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu).Preference is given toO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate(HATU).

Suitable bases for process step (II)+(III)→(I), if X¹ representshydroxyl, are, for example, alkali metal carbonates such as sodiumcarbonate or potassium carbonate, or sodium bicarbonate or potassiumbicarbonate, or organic bases such as trialkylamines, for exampletriethylamine, N-methylmorpholine, N-methylpiperidine,4-dimethylaminopyridine or diisopropylethylamine. The condensation ispreferably carried out using diisopropylethylamine.

The compounds of the formula (II) and (III) are either commerciallyavailable, known from the literature, or can be prepared from readilyavailable starting materials by adaptation of standard methods describedin the literature. Detailed procedures and literature references forpreparing the starting materials can also be found in the ExperimentalPart in the section on the preparation of the starting materials andintermediates.

The preparation of the compounds of the invention may be illustrated bymeans of the following synthetic scheme:

The compounds of general formula (I) of the present invention can beconverted to any salt, preferably pharmaceutically acceptable salts, asdescribed herein, by any method which is known to the person skilled inthe art. Similarly, any salt of a compound of general formula (I) of thepresent invention can be converted into the free compound, by any methodwhich is known to the person skilled in the art.

The compounds of the present invention have valuable pharmacologicalproperties and can be used for the prevention and/or treatment ofvarious diseases and disease-induced states in humans and other mammals.Compounds of general formula (I) of the present invention demonstrate avaluable pharmacological spectrum of action and pharmacokinetic profile,both of which could not have been predicted. Compounds of the presentinvention have surprisingly been found to effectively inhibit thevasopressin Via receptor and it is possible therefore that saidcompounds be used for the treatment and/or prevention of diseases,preferably renal and cardiovascular diseases in humans and animals.

In the context of the present invention, the term “treatment” or“treating” includes inhibiting, delaying, relieving, mitigating,arresting, reducing, or causing the regression of a disease, disorder,condition, or state, the development and/or progression thereof, and/orthe symptoms thereof. The term “prevention” or “preventing” includesreducing the risk of having, contracting, or experiencing a disease,disorder, condition, or state, the development and/or progressionthereof, and/or the symptoms thereof. The term prevention includesprophylaxis. Treatment or prevention of a disorder, disease, condition,or state may be partial or complete.

Throughout this document, for the sake of simplicity, the use ofsingular language is given preference over plural language, but isgenerally meant to include the plural language if not otherwise stated.For example, the expression “A method of treating a disease in apatient, comprising administering to a patient an effective amount of acompound of the general formula (I)” is meant to include thesimultaneous treatment of more than one disease as well as theadministration of more than one compound of the general formula (I).

The compounds of the present invention are highly potent and inparticular selective antagonists of the vasopressin Via receptor. Thecompounds of the invention are therefore expected to be highly valuableas therapeutic agents for the treatment and/or prevention of diseases,in particular for the treatment and/or prevention of renal andcardiovascular diseases.

As used herein, the term “vasopressin Via receptor antagonist” refers toa compound that functions by inhibiting (partially or completely) orblocking the vasopressin Via receptor, thereby preventing activation ofthe receptor by vasopressin.

In one embodiment, compounds described herein are active at the V1areceptor. In another embodiment compounds described herein exhibitinhibition of the V1a receptor according to the study in B-1 with anIC₅₀<100 nM. In another embodiment compounds described herein exhibitinhibition of the V1a receptor according to the study in B-1 with anIC₅₀<20 nM. In another embodiment compounds described herein exhibitinhibition of the V1a receptor according to the study in B-1 with anIC₅₀<10 nM.

In a further embodiment, compounds described herein are selectivelyactive at the V1a receptor, and are less active, substantially lessactive, and/or inactive at other vasopressin receptors, such as the V1band/or V2 subtypes. In another embodiment, compounds described hereinare at least 10-fold selective for the V1a receptor compared to the V2receptor as determined according to the study in B-1. In anotherembodiment, compounds described herein are at least 15-fold selectivefor the V1a receptor compared to the V2 receptor as determined accordingto the study in B-1. In another embodiment, compounds described hereinare at least 20-fold selective for the Via receptor compared to the V2receptor as determined according to the study in B-1. In anotherembodiment, compounds described herein are at least 30-fold selectivefor the V1a receptor compared to the V2 receptor as determined accordingto the study in B-1.

The compounds according to the invention are suitable for the treatmentand/or prevention of renal diseases, in particular of acute and chronickidney diseases, diabetic kidney diseases, and of acute and chronicrenal failure. The general terms ‘renal disease’ or ‘kidney disease’describe a class of conditions in which the kidneys fail to filter andremove waste products from the blood. There are two major forms ofkidney disease: acute kidney disease (acute kidney injury, AKI) andchronic kidney disease (CKD). The compounds according to the inventionmay further be used for the treatment and/or prevention of sequelae ofacute kidney injury arising from multiple insults such asischemia-reperfusion injury, radiocontrast administration,cardiopulmonary bypass surgery, shock and sepsis. In the sense of thepresent invention, the term renal failure or renal insufficiencycomprises both acute and chronic manifestations of renal insufficiency,as well as underlying or related kidney diseases such as renalhypoperfusion, intradialytic hypotension, obstructive uropathy,glomerulopathies, IgA nephropathy, glomerulonephritis, acuteglomerulonephritis, glomerulosclerosis, tubulointerstitial diseases,nephropathic diseases such as primary and congenital kidney disease,nephritis, Alport syndrome, kidney inflammation, immunological kidneydiseases such as kidney transplant rejection, immune complex-inducedkidney diseases, nephropathy induced by toxic substances, contrastmedium-induced nephropathy; minimal change glomerulonephritis (lipoid);Membranous glomerulonephritis; focal segmental glomerulosclerosis(FSGS); hemolytic uremic syndrome (HUS), amyloidosis, Goodpasture'ssyndrome, Wegener's granulomatosis, Purpura Schonlein-Henoch, diabeticand non-diabetic nephropathy, pyelonephritis, renal cysts,nephrosclerosis, hypertensive nephrosclerosis and nephrotic syndrome,which can be characterized diagnostically, for example, by abnormallyreduced creatinine and/or water excretion, abnormally increased bloodconcentrations of urea, nitrogen, potassium and/or creatinine, alteredactivity of renal enzymes such as, for example, glutamyl synthetase,altered urine osmolarity or urine volume, increased microalbuminuria,macroalbuminuria, lesions of glomeruli and arterioles, tubulardilatation, hyperphosphataemia and/or the need for dialysis. The presentinvention also comprises the use of the compounds according to theinvention for the treatment and/or prevention of sequelae of renalinsufficiency, for example pulmonary edema, heart failure, uraemia,anaemia, electrolyte disturbances (e.g. hyperkalaemia, hyponatraemia)and disturbances in bone and carbohydrate metabolism. The compoundsaccording to the invention are also suitable for the treatment and/orprevention of polycystic kidney disease (PCKD) and of the syndrome ofinadequate ADH secretion (SIADH).

Cardiovascular diseases in this context that may be treated and/orprevented with the compounds of the invention include, but are notlimited to, the following: acute and chronic heart failure includingworsening chronic heart failure (or hospitalization for heart failure)and including congestive heart failure, arterial hypertension, resistanthypertension, arterial pulmonary hypertension, coronary heart disease,stable and unstable angina pectoris, atrial and ventricular arrhythmias,disturbances of atrial and ventricular rhythm and conductiondisturbances, for example atrioventricular blocks of degree I-III (AVBI-III), supraventricular tachyarrhythmia, atrial fibrillation, atrialflutter, ventricular fibrillation, ventricular flutter, ventriculartachyarrhythmia, torsade-de-pointes tachycardia, atrial and ventricularextrasystoles, AV-junction extrasystoles, sick-sinus syndrome, syncopes,AV-node re-entry tachycardia and Wolff-Parkinson-White syndrome, acutecoronary syndrome (ACS), autoimmune heart diseases (pericarditis,endocarditis, valvulitis, aortitis, cardiomyopathies), shock such ascardiogenic shock, septic shock and anaphylactic shock, aneurysms, Boxercardiomyopathy (premature ventricular contraction), furthermorethromboembolic diseases and ischaemias such as peripheral perfusiondisturbances, reperfusion injury, arterial and venous thromboses,myocardial insufficiency, endothelial dysfunction, micro- andmacrovascular damage (vasculitis) and for preventing restenoses such asafter thrombolysis therapies, percutaneous transluminal angioplasty(PTA), percutaneous transluminal coronary angioplasty (PTCA), hearttransplantation and bypass operations, arteriosclerosis, disturbances oflipid metabolism, hypolipoproteinaemias, dyslipidemias,hypertriglyceridemias, hyperlipidemias and combined hyperlipidemias,hyper-cholesterolaemias, abetalipoproteinaemia, sitosterolemia,xanthomatosis, Tangier disease, adipositas, obesity, metabolic syndrome,transitory and ischemic attacks, stroke, inflammatory cardiovasculardiseases, peripheral and cardiac vascular diseases, peripheralcirculation disorders, spasms of the coronary arteries and peripheralarteries, and edema such as, for example, pulmonary edema, cerebraledema, renal edema and heart failure-related edema.

In the sense of the present invention, the term heart failure alsoincludes more specific or related disease forms such as right heartfailure, left heart failure, global insufficiency, ischemiccardiomyopathy, dilatative cardiomyopathy, congenital heart defects,heart valve defects, heart failure with heart valve defects, mitralvalve stenosis, mitral valve insufficiency, aortic valve stenosis,aortic valve insufficiency, tricuspidal stenosis, tricuspidalinsufficiency, pulmonary valve stenosis, pulmonary valve insufficiency,combined heart valve defects, heart muscle inflammation (myocarditis),chronic myocarditis, acute myocarditis, viral myocarditis, diabeticheart failure, alcohol-toxic cardiomyopathy, cardiac storage diseases,heart failure with preserved ejection fraction (HFpEF or diastolic heartfailure), and heart failure with reduced ejection fraction (HFrEF orsystolic heart failure).

The compounds of the present invention may be particularly useful forthe treatment and/or prevention of the cardiorenal syndrome (CRS) andits various subtypes. This term embraces certain disorders of the heartand kidneys whereby acute or chronic dysfunction in one organ may induceacute or chronic dysfunction of the other.

Moreover, the compounds according to the invention may be used for thetreatment and/or prevention of peripheral arterial disease (PAD)including claudication and including critical limb ischemia as well ascoronary microvascular dysfunction (CMD) including CMD type 1-4, primaryand secondary Raynaud's phenomenon, microcirculation disturbances,claudication, peripheral and autonomic neuropathies, diabeticmicroangiopathies, diabetic retinopathy, diabetic limb ulcers, gangrene,CREST syndrome, erythematous disorders, rheumatic diseases and forpromoting wound healing.

Furthermore, the compounds of the invention are suitable for treatingurological diseases and diseases of the male and female urogenitalsystem such as, for example, benign prostatic syndrome (BPS), benignprostatic hyperplasia (BPH), benign prostatic enlargement (BPE), bladderoutlet obstruction (BOO), lower urinary tract syndromes (LUTS),neurogenic overactive bladder (OAB), interstitial cystitis (IC), urinaryincontinence (UI) such as, for example, mixed, urge, stress and overflowincontinence (MUI, UUI, SUI, OUI), pelvic pains, erectile dysfunction,dysmenorrhea and endometriosis.

The compounds according to the invention may also be used for thetreatment and/or prevention of inflammatory diseases, asthmaticdiseases, chronic obstructive pulmonary disease (COPD), acuterespiratory distress syndrome (ARDS), acute lung injury (ALI),alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonaryemphysema (e.g. smoking-induced pulmonary emphysema) and cystic fibrosis(CF). In addition, the compounds of the invention may be used for thetreatment and/or prevention of pulmonary arterial hypertension (PAH) andother forms of pulmonary hypertension (PH), including pulmonaryhypertension associated with left ventricular disease, HIV infection,sickle cell anaemia, thromboembolism (CTEPH), sarcoidosis, chronicobstructive pulmonary disease (COPD) or pulmonary fibrosis.

Additionally, the compounds according to the invention may be used forthe treatment and/or prevention of liver cirrhosis, ascites, diabetesmellitus and diabetic complications such as, for example, neuropathy andnephropathy.

Further, the compounds of the invention are suitable for the treatmentand/or prevention of central nervous disorders such as anxiety states,depression, glaucoma, cancer such as in particular pulmonary tumors, andcircadian rhythm misalignment such as jet lag and shift work.

Furthermore, the compounds according to the invention may be useful forthe treatment and/or prevention of pain conditions, diseases of theadrenals such as, for example, pheochromocytoma and adrenal apoplexy,diseases of the intestine such as, for example, Crohn's disease anddiarrhea, menstrual disorders such as, for example, dysmenorrhea,endometriosis, preterm labor and tocolysis.

Due to their activity and selectivity profile, the compounds of thepresent invention are believed to be particularly suitable for thetreatment and/or prevention of acute and chronic kidney diseasesincluding diabetic nephropathy, acute and chronic heart failure,preeclampsia, peripheral arterial disease (PAD), coronary microvasculardysfunction (CMD), Raynaud's syndrome and dysmenorrhea.

The diseases mentioned above have been well characterized in humans, butalso exist with a com-parable etiology in other mammals, and may betreated in those with the compounds and methods of the presentinvention.

Thus, the present invention further relates to the use of the compoundsaccording to the invention for the treatment and/or prevention ofdiseases, especially of the aforementioned diseases.

The present invention further relates to the use of the compoundsaccording to the invention for preparing a pharmaceutical compositionfor the treatment and/or prevention of diseases, especially of theaforementioned diseases.

The present invention further relates to the use of the compoundsaccording to the invention in a method for the treatment and/orprevention of diseases, especially of the aforementioned diseases.

The present invention further relates to a method for the treatmentand/or prevention of diseases, especially of the aforementioneddiseases, by using an effective amount of at least one of the compoundsaccording to the invention.

In accordance with another aspect, the present invention coverspharmaceutical combinations, in particular medicaments, comprising atleast one compound of general formula (I) of the present invention andat least one or more further active ingredients, in particular for thetreatment and/or prevention of diseases, especially of theaforementioned diseases.

Particularly, the present invention covers a pharmaceutical combination,which comprises:

-   -   one or more first active ingredients, in particular compounds of        general formula (I) as defined aforementioned, and    -   one or more further active ingredients, in particular for the        treatment and/or prevention of diseases, especially of the        aforementioned diseases.

The term “combination” in the present invention is used as known topersons skilled in the art, it being possible for said combination to bea fixed combination, a non-fixed combination or a kit-of-parts.

A “fixed combination” in the present invention is used as known topersons skilled in the art and is defined as a combination wherein, forexample, a first active ingredient, such as one or more compounds ofgeneral formula (I) of the present invention, and a further activeingredient are present together in one unit dosage or in one singleentity. One example of a “fixed combination” is a pharmaceuticalcomposition wherein a first active ingredient and a further activeingredient are present in admixture for simultaneous administration,such as in a formulation. Another example of a “fixed combination” is apharmaceutical combination wherein a first active ingredient and afurther active ingredient are present in one unit without being inadmixture.

A non-fixed combination or “kit-of-parts” in the present invention isused as known to persons skilled in the art and is defined as acombination wherein a first active ingredient and a further activeingredient are present in more than one unit. One example of a non-fixedcombination or kit-of-parts is a combination wherein the first activeingredient and the further active ingredient are present separately. Itis possible for the components of the non-fixed combination orkit-of-parts to be administered separately, sequentially,simultaneously, concurrently or chronologically staggered.

The compounds of the present invention can be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutically active ingredients where the combination causes nounacceptable adverse effects. The present invention also covers suchpharmaceutical combinations. For example, the compounds of the presentinvention can be combined with known agents for the treatment and/orprevention of diseases, especially of the aforementioned diseases.

In particular, the compounds of the present invention may be used infixed or separate combination with

-   -   antithrombotic agents, for example and preferably from the group        of platelet aggregation inhibitors, anticoagulants and        profibrinolytic substances;    -   blood pressure lowering agents, for example and preferably from        the group of calcium antagonists, angiotensin AII antagonists,        ACE inhibitors, NEP inhibitors, vasopeptidase inhibitors,        endothelin antagonists, renin inhibitors, alpha-blockers,        beta-blockers, mineralocorticoid receptor antagonists and        diuretics;    -   antidiabetic agents (hypoglycemic or antihyperglycemic agents),        such as for example and preferably insulin and derivatives,        sulfonylureas, biguanides, thiazolidinediones, acarbose, DPP4        inhibitors, GLP-1 analogues, or SGLT inhibitors (gliflozins).    -   organic nitrates and NO-donors, for example sodium        nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide        dinitrate, molsidomine or SIN-1, and inhalational NO;        -   compounds that inhibit the degradation of cyclic guanosine            monophosphate (cGMP), for example inhibitors of            phosphodiesterases (PDE) 1, 2, 5 and/or 9, in particular            PDE-5 inhibitors such as sildenafil, vardenafil, tadalafil,            udenafil, dasantafil, avanafil, mirodenafil, lodenafil,            CTP-499 or PF-00489791;    -   positive-inotropic agents, such as for example cardiac        glycosides (digoxin) and beta-adrenergic and dopaminergic        agonists such as isoproterenol, adrenalin, noradrenalin,        dopamine or dobut-amine;    -   natriuretic peptides, such as for example atrial natriuretic        peptide (ANP, anaritide), B-type natriuretic peptide or brain        natriuretic peptide (BNP, nesiritide), C-type natriuretic        peptide (CNP) or urodilatin;    -   calcium sensitizers, such as for example and preferably        levosimendan;    -   NO- and heme-independent activators of soluble guanylate cyclase        (sGC for example and with preference the compounds described in        WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462        and WO 02/070510;    -   NO-independent, but heme-dependent stimulators of guanylate        cyclase (sGC), for example and with preference the compounds        described in WO 00/06568, WO 00/06569, WO 02/42301, WO        03/095451, WO 2011/147809, WO 2012/004258, WO 2012/028647 and WO        2012/059549;    -   agents, that stimulates the synthesis of cGMP, for example and        with preference sGC modulators, for example and with preference        riociguat, cinaciguat, vericiguat or BAY 1101042;    -   inhibitors of human neutrophil elastase (HNE), such as for        example sivelestat or DX-890 (reltran);    -   compounds inhibiting the signal transduction cascade, in        particular tyrosine and/or serine/threo-nine kinase inhibitors,        such as for example nintedanib, dasatinib, nilotinib, bosutinib,        regora-fenib, sorafenib, sunitinib, cediranib, axitinib,        telatinib, imatinib, brivanib, pazopanib, vatalanib, gefitinib,        erlotinib, lapatinib, canertinib, lestaurtinib, pelitinib,        semaxanib or tandutinib;        -   compounds influencing the energy metabolism of the heart,            such as for example and preferably etomoxir,            dichloroacetate, ranolazine or trimetazidine, or full or            partial adenosine A1 receptor agonists as GS-9667            (previously known as CVT-3619), capadenoson and neladenoson            bialanate (BAY 1067197);    -   compounds influencing the heart rate, such as for example and        preferably ivabradine;    -   cardiac myosin activators, such as for example and preferably        omecamtiv mecarbil (CK-1827452);        -   anti-inflammatory drugs such as non-steroidal            anti-inflammatory drugs (NSAIDs) including acetylsalicylic            acid (aspirin), ibuprofen and naproxen, glucocorticoids such            as for example and preferably prednison, prednisolon,            methylprednisolon, triamcinolon, dexamethason,            beclomethason, betamethason, flunisolid, budesonid or            fluticason, or 5-aminosalicylic acid derivatives,            leukotriene antagonists, TNF-alpha inhibitors and chemokine            receptor antagonists such as CCR1, 2 and/or 5 inhibitors;    -   fat metabolism altering agents, for example and preferably from        the group of thyroid receptor agonists, cholesterol synthesis        inhibitors, such as for example and preferably HMG-CoA-reductase        or squalene synthesis inhibitors, ACAT inhibitors, CETP        inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or        PPAR-delta agonists, cholesterol absorption inhibitors, lipase        inhibitors, polymeric bile acid adsorbers, bile acid        reabsorption inhibitors and lipoprotein(a) antagonists.

Antithrombotic agents are preferably to be understood as compounds fromthe group of platelet aggregation inhibitors, anticoagulants andprofibrinolytic substances.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a plateletaggregation inhibitor, for example and preferably aspirin, clopidogrel,ticlopidine or dipyridamole.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thrombin inhibitor,for example and preferably ximelagatran, dabigatran, melagatran,bivalirudin or enoxaparin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a GPIIb/IIIaantagonist, for example and preferably tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a factor Xainhibitor, for example and preferably rivaroxaban, apixaban, otamixaban,fidexaban, razaxaban, fondaparinux, idraparinux, DU-176b, PMD-3112,YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with heparin or a lowmolecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a vitamin Kantagonist, for example and preferably coumarin.

Blood pressure lowering agents are preferably to be understood ascompounds from the group of calcium antagonists, angiotensin AIIantagonists, ACE inhibitors, NEP inhibitors, vasopeptidase inhibitors,endothelin antagonists, renin inhibitors, alpha-blockers, beta-blockers,mineralocorticoid receptor antagonists and diuretics.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a calcium antagonist,for example and preferably nifedipine, amlodipine, verapamil ordiltiazem.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an alpha-1-receptorblocker, for example and preferably prazosin or tam-sulosin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a beta-blocker, forexample and preferably propranolol, atenolol, timolol, pindolol,alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol,mepindolol, carazolol, sotalol, metoprolol, betaxolol, celiprolol,bisoprolol, carteolol, esmolol, labetalol, carve-dilol, adaprolol,landiolol, nebivolol, epanolol or bucindolol.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an angiotensin AIIreceptor antagonist, for example and preferably losar-tan, candesartan,valsartan, telmisartan, irbesartan, olmesartan, eprosartan, embursartanor azilsartan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a vasopeptidaseinhibitor or inhibitor of neutral endopeptidase (NEP), such as forexample and preferably sacubitril, omapatrilat or AVE-7688.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a dual angiotensinAII receptor antagonist/NEP inhibitor (ARNI), for example and preferablyLCZ696.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACE inhibitor, forexample and preferably enalapril, captopril, lisino-pril, ramipril,delapril, fosinopril, quinopril, perindopril, benazepril or trandopril.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an endothelinantagonist, for example and preferably bosentan, darusen-tan,ambrisentan, tezosentan, sitaxsentan, avosentan, macitentan oratrasentan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a renin inhibitor,for example and preferably aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a mineralocorticoidreceptor antagonist, for example and preferably fine-renone,spironolactone, canrenone, potassium canrenoate, eplerenone, esaxerenone(CS-3150), or apararenone (MT-3995), CS-3150, or MT-3995.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a diuretic, such asfor example and preferably furosemide, bumetanide, piretanide,torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide,xipamide, indapa-mide, hydroflumethiazide, methyclothiazide,polythiazide, trichloromethiazide, chlorothalidone, metolazone,quinethazone, acetazolamide, dichlorophenamide, methazolamide,glycerine, isosorbide, mannitol, amiloride or triamterene.

Fat metabolism altering agents are preferably to be understood ascompounds from the group of CETP inhibitors, thyroid receptor agonists,cholesterol synthesis inhibitors such as HMG-CoA-reductase or squalenesynthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha,PPAR-gamma and/or PPAR-delta agonists, cholesterol absorptioninhibitors, polymeric bile acid adsorbers, bile acid reabsorptioninhibitors, lipase inhibitors and lipoprotein(a) antagonists.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a CETP inhibitor, forexample and preferably dalcetrapib, anacetrapib, BAY 60-5521 orCETP-vaccine (Avant).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thyroid receptoragonist, for example and preferably D-thyroxin, 3,5,3′-triiodothyronin(T3), CGS 23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an HMG-CoA-reductaseinhibitor from the class of statins, for example and preferablylovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin,rosuvastatin or pitava-statin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a squalene synthesisinhibitor, for example and preferably BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACAT inhibitor,for example and preferably avasimibe, melinamide, pactimibe, eflucimibeor SMP-797.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an MTP inhibitor, forexample and preferably implitapide, R-103757, BMS-201038 or JTT-130.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-gamma agonist,for example and preferably pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-delta agonist,for example and preferably GW 501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a cholesterolabsorption inhibitor, for example and preferably ezetimibe, tiqueside orpamaqueside.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a lipase inhibitor,for example and preferably orlistat.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a polymeric bile acidadsorber, for example and preferably cholestyr-amine, colestipol,colesolvam, CholestaGel or colestimide.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a bile acidreabsorption inhibitor, for example and preferably ASBT (=IBAT)inhibitors such as AZD-7806, S-8921, AK-105, BARI-1741, SC-435 orSC-635.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a lipoprotein(a)antagonist, for example and preferably gemcabene calcium (CI-1027) ornicotinic acid.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a TGFbeta antagonist,by way of example and with preference pirfenidone or fresolimumab.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with HIF-PH inhibitors, byway of example and with preference molidustat or roxadustat.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a CCR2 antagonist, byway of example and with preference CCX-140.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a TNFalphaantagonist, by way of example and with preference adalimumab.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a galectin-3inhibitor, by way of example and with preference GCS-100.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a BMP-7 agonist, byway of example and with preference THR-184.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a NOX1/4 inhibitor,by way of example and with preference GKT-137831.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a medicament whichaffects the vitamin D metabolism, by way of example and with preferencecholecalciferol or paracalcitol.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a cytostatic agent,by way of example and with preference cyclophosphamide.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an immunosuppressiveagent, by way of example and with preference ciclosporin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a phosphate binder,by way of example and with preference sevelamer or lanthanum carbonate.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a calcimimetic fortherapy of hyperparathyroidism.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with agents for irondeficit therapy, by way of example and with preference iron products.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with agents for thetherapy of hyperurikaemia, by way of example and with preferenceallopurinol or rasburicase.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with glycoprotein hormonefor the therapy of anaemia, by way of example and with preferenceerythropoietin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with biologics for immunetherapy, by way of example and with preference abatacept, rituximab,eculizumab or belimumab.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with Jak inhibitors, byway of example and with preference ruxolitinib, tofacitinib,baricitinib, CYT387, GSK2586184, lestaurtinib, pacritinib (SB1518) orTG101348.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with prostacyclin analogsfor therapy of microthrombi.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an alkali therapy, byway of example and with preference sodium bicarbonate.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an mTOR inhibitor, byway of example and with preference everolimus or rapamycin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an NHE3 inhibitor, byway of example and with preference AZD1722.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an eNOS modulator, byway of example and with preference sapropterin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a CTGF inhibitor, byway of example and with preference FG-3019.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with antidiabetics(hypoglycemic or antihyperglycemic agents), such as for example andpreferably insulin and derivatives, sulfonylureas such as tolbutamide,carbutamide, acetohexamide, chlorpropamide, glipizide, gliclazide,glibenclamide, glyburide, glibornuride, gliquidone, glisoxepide,glyclopyramide, glimepiride, JB253 and JB558, meglitinides such asrepaglinide and nateglinide, biguanides such as metformin and buformin,thiazolidinediones such as rosiglitazone and pioglitazone,alpha-glucosidase inhibitors such as miglitol, acarbose and voglibose,DPP4 inhibitors such as vildagliptin, sitagliptin, saxagliptin,linagliptin, alogliptin, septagliptin and teneligliptin, GLP-1 analoguessuch as exenatide (also exendin-4, liraglutide, lixisenatide andtaspoglutide, or SGLT inhibitors (gliflozins) such as canagliflozin,dapagliflozin and empagliflozin.

In a particularly preferred embodiment, the compounds of the presentinvention are administered in combination with one or more additionaltherapeutic agents selected from the group consisting of diuretics,angiotensin AII antagonists, ACE inhibitors, beta-receptor blockers,mineralocorticoid receptor antagonists, antidiabetics, organic nitratesand NO donors, activators and stimulators of the soluble guanylatecyclase (sGC), and positive-inotropic agents.

In a further particularly preferred embodiment, the compounds of thepresent invention are administered in combination with one or moreadditional therapeutic agents selected from the group consisting ofdiuretics, angiotensin AII antagonists, ACE inhibitors, beta-receptorblockers, mineralocorticoid receptor antagonists, antidiabetics, organicnitrates and NO donors, activators and stimulators of the solubleguanylate cyclase (sGC), positive-inotropic agents, antiinflammatoryagents, immunosuppressive agents, phosphate binders and/or compoundswhich modulate vitamin D metabolism.

Thus, in a further embodiment, the present invention relates topharmaceutical compositions comprising at least one of the compoundsaccording to the invention and one or more additional therapeutic agentsfor the treatment and/or prevention of diseases, especially of theaforementioned diseases.

Furthermore, the compounds of the present invention may be utilized, assuch or in compositions, in research and diagnostics, or as analyticalreference standards and the like, which are well known in the art.

When the compounds of the present invention are administered aspharmaceuticals, to humans and other mammals, they can be given per seor as a pharmaceutical composition containing, for example, 0.1% to99.5% (more preferably, 0.5% to 90%) of active ingredient in combinationwith one or more pharmaceutically acceptable excipients.

Thus, in another aspect, the present invention relates to pharmaceuticalcompositions comprising at least one of the compounds according to theinvention, conventionally together with one or more inert, non-toxic,pharmaceutically acceptable excipients, and to the use thereof for thetreatment and/or prevention of diseases, especially of theaforementioned diseases.

It is possible for the compounds according to the invention to havesystemic and/or local activity.

For this purpose, they can be administered in a suitable manner, suchas, for example, via the oral, parenteral, pulmonary, nasal, sublingual,lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival,otic route or as an implant or stent.

For these administration routes, it is possible for the compoundsaccording to the invention to be administered in suitable administrationforms.

For oral administration, it is possible to formulate the compoundsaccording to the invention to dosage forms known in the art that deliverthe compounds of the invention rapidly and/or in a modified manner, suchas, for example, tablets (uncoated or coated tablets, for example withenteric or controlled release coatings that dissolve with a delay or areinsoluble), orally-disintegrating tablets, films/wafers,films/lyophylisates, capsules (for example hard or soft gelatinecapsules), sugar-coated tablets, granules, pellets, powders, emulsions,suspensions, aerosols or solutions. It is possible to incorporate thecompounds according to the invention in crystalline and/or amorphisedand/or dissolved form into said dosage forms.

Parenteral administration can be effected with avoidance of anabsorption step (for example intravenous, intraarterial, intracardial,intraspinal or intralumbal) or with inclusion of absorption (for exampleintramuscular, subcutaneous, intracutaneous, percutaneous orintraperitoneal).

Administration forms which are suitable for parenteral administrationare, inter alia, preparations for injection and infusion in the form ofsolutions, suspensions, emulsions, lyophylisates or sterile powders.

Examples which are suitable for other administration routes arepharmaceutical forms for inhalation [inter alia powder inhalers,nebulizers], nasal drops, nasal solutions, nasal sprays;tablets/films/wafers/capsules for lingual, sublingual or buccaladministration; suppositories; eye drops, eye ointments, eye baths,ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, eartampons; vaginal capsules, aqueous suspensions (lotions, mixturaeagitandae), lipophilic suspensions, emulsions, ointments, creams,transdermal therapeutic systems (such as, for example, patches), milk,pastes, foams, dusting powders, implants or stents.

The compounds according to the invention can be incorporated into thestated administration forms. This can be effected in a manner known perse by mixing with pharmaceutically suitable excipients. Pharmaceuticallysuitable excipients include, inter alia,

-   -   fillers and carriers (for example cellulose, microcrystalline        cellulose (such as, for example, Avicel®), lactose, mannitol,        starch, calcium phosphate (such as, for example, Di-Cafos®)),    -   ointment bases (for example petroleum jelly, paraffins,        triglycerides, waxes, wool wax, wool wax alcohols, lanolin,        hydrophilic ointment, polyethylene glycols),    -   bases for suppositories (for example polyethylene glycols, cacao        butter, hard fat),    -   solvents (for example water, ethanol, iso-propanol, glycerol,        propylene glycol, medium chain-length triglycerides fatty oils,        liquid polyethylene glycols, paraffins),    -   surfactants, emulsifiers, dispersants or wetters (for example        sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols        (such as, for example, Lanette®), sorbitan fatty acid esters        (such as, for example, Span®), polyoxyethylene sorbitan fatty        acid esters (such as, for example, Tween®), polyoxyethylene        fatty acid glycerides (such as, for example, Cremophor®),        polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol        ethers, glycerol fatty acid esters, poloxamers (such as, for        example, Pluronic®),    -   buffers, acids and bases (for example phosphates, carbonates,        citric acid, acetic acid, hydrochloric acid, sodium hydroxide        solution, ammonium carbonate, trometamol, triethanolamine),    -   isotonicity agents (for example glucose, sodium chloride),    -   adsorbents (for example highly-disperse silicas),    -   viscosity-increasing agents, gel formers, thickeners and/or        binders (for example polyvinylpyrrolidone, methylcellulose,        hydroxypropylmethylcellulose, hydroxypropyl-cellulose,        carboxymethylcellulose-sodium, starch, carbomers, polyacrylic        acids (such as, for example, Carbopol®); alginates, gelatine),    -   disintegrants (for example modified starch,        carboxymethylcellulose-sodium, sodium starch glycolate (such as,        for example, Explotab®), cross-linked polyvinylpyrrolidone,        croscarmellose-sodium (such as, for example, AcDiSol®)),    -   flow regulators, lubricants, glidants and mould release agents        (for example magnesium stearate, stearic acid, talc,        highly-disperse silicas (such as, for example, Aerosil®)),    -   coating materials (for example sugar, shellac) and film formers        for films or diffusion membranes which dissolve rapidly or in a        modified manner (for example polyvinylpyrrolidones (such as, for        example, Kollidon®), polyvinyl alcohol,        hydroxypropylmethylcellulose, hydroxypropylcellulose,        ethylcellulose, hydroxypropyl-methylcellulose phthalate,        cellulose acetate, cellulose acetate phthalate, polyacrylates,        polymethacrylates such as, for example, Eudragit®)),    -   capsule materials (for example gelatine,        hydroxypropylmethylcellulose),    -   synthetic polymers (for example polylactides, polyglycolides,        polyacrylates, polymethacrylates (such as, for example,        Eudragit®), polyvinylpyrrolidones (such as, for example,        Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene        oxides, polyethylene glycols and their copolymers and        blockcopolymers),    -   plasticizers (for example polyethylene glycols, propylene        glycol, glycerol, triacetine, triacetyl citrate, dibutyl        phthalate),    -   penetration enhancers,    -   stabilisers (for example antioxidants such as, for example,        ascorbic acid, ascorbyl palmitate, sodium ascorbate,        butylhydroxyanisole, butylhydroxytoluene, propyl gallate),    -   preservatives (for example parabens, sorbic acid, thiomersal,        benzalkonium chloride, chlorhexidine acetate, sodium benzoate),    -   colourants (for example inorganic pigments such as, for example,        iron oxides, titanium dioxide),    -   flavourings, sweeteners, flavour- and/or odour-masking agents.

The present invention furthermore relates to a pharmaceuticalcomposition which comprise at least one compound according to theinvention, conventionally together with one or more pharmaceuticallysuitable excipient(s), and to their use according to the presentinvention.

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment of cardiovascular and renal disorders, bystandard toxicity tests and by standard pharmacological assays for thedetermination of treatment of the conditions identified above inmammals, and by comparison of these results with the results of knownactive ingredients or medicaments that are used to treat theseconditions, the effective dosage of the compounds of the presentinvention can readily be determined for treatment of each desiredindication. The amount of the active ingredient to be administered inthe treatment of one of these conditions can vary widely according tosuch considerations as the particular compound and dosage unit employed,the mode of administration, the period of treatment, the age and sex ofthe patient treated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 200 mg/kg body weightper day, and preferably from about 0.01 mg/kg to about 20 mg/kg bodyweight per day. Clinically useful dosing schedules will range from oneto three times a day dosing to once every four weeks dosing. Inaddition, it is possible for “drug holidays”, in which a patient is notdosed with a drug for a certain period of time, to be beneficial to theoverall balance between pharmacological effect and tolerability. It ispossible for a unit dosage to contain from about 0.5 mg to about 1500 mgof active ingredient, and can be administered one or more times per dayor less than once a day. The average daily dosage for administration byinjection, including intravenous, intramuscular, subcutaneous andparenteral injections, and use of infusion techniques will preferably befrom 0.01 to 200 mg/kg of total body weight. Illustratively, thecompound of the present invention may be administered parenterally at adose of about 0.001 mg/kg to about 10 mg/kg, preferably of about 0.01mg/kg to about 1 mg/kg of body weight. In oral administration, anexemplary dose range is about 0.01 to 100 mg/kg, preferably about 0.01to 20 mg/kg, and more preferably about 0.1 to 10 mg/kg of body weight.Ranges intermediate to the above-recited values are also intended to bepart of the invention.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt or ester or composition thereofcan be ascertained by those skilled in the art using conventionaltreatment tests.

The following exemplary embodiments illustrate the invention. Theinvention is not restricted to the examples.

The percentages in the following tests and examples are, unless statedotherwise, by weight; parts are by weight. Solvent ratios, dilutionratios and concentrations reported for liquid/liquid solutions are eachbased on volume.

EXPERIMENTAL SECTION General Part

NMR peak forms are stated as they appear in the spectra, possible higherorder effects have not been considered.

Chemical names were generated using the ACD/Name software from ACD/Labs.In some cases generally accepted names of commercially availablereagents were used in place of ACD/Name generated names.

The following table 1 lists the abbreviations used in this paragraph andin the Examples section as far as they are not explained within the textbody. Other abbreviations have their meanings customary per se to theskilled person.

TABLE 1 Abbreviations The following table lists the abbreviations usedherein. Abbreviation Meaning abs absolut br broad (¹H-NMR signal) conc.concentrated CI chemical ionisation d doublet (¹H-NMR signal) d day(s)DAD diode array detector DCM dichloromethane dd double-doubletDess-Martin 1,1,1-Triacetoxy-1,1-dihydro-1,2- periodinanebenziodoxol-3(1H)-one DMSO dimethylsulfoxide ESI electrospray (ES)ionisation h hour(s) HATU1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium3-oxide hexafluorophosphate HPLC high performance liquid chromatographyLC-MS liquid chromatography mass spectrometry m multiplet (¹H-NMRsignal) min minute(s) MS mass spectrometry MTBE methyl-tert-butyletherNMR nuclear magnetic resonance spectroscopy: chemical shifts (δ) aregiven in ppm. The chemical shifts were corrected by setting the DMSOsignal to 2.50 ppm unless otherwise stated. of th. of theory PDA PhotoDiode Array R_(t) retention time (as measured either with HPLC or UPLC)in minutes s singlet (¹H-NMR signal) SFC Supercritical FluidChromatography SQD Single-Quadrupole-Detector t triplet (¹H-NMR signal)td triple-doublet (¹H-NMR signal) TFA trifluoroacetic acid THFtetrahydrofuran UPLC ultra performance liquid chromatography

The various aspects of the invention described in this application areillustrated by the following examples which are not meant to limit theinvention in any way.

The example testing experiments described herein serve to illustrate thepresent invention and the invention is not limited to the examplesgiven.

All reagents, for which the synthesis is not described in theexperimental part, are either commercially available, or are knowncompounds or may be formed from known compounds by known methods by aperson skilled in the art.

The compounds and intermediates produced according to the methods of theinvention may require purification. Purification of organic compounds iswell known to the person skilled in the art and there may be severalways of purifying the same compound. In some cases, no purification maybe necessary. In some cases, the compounds may be purified bycrystallization. In some cases, impurities may be stirred out using asuitable solvent. In some cases, the compounds may be purified bychromatography, particularly flash column chromatography, using forexample prepacked silica gel cartridges, e.g. Biotage SNAP cartidgesKP-Sil® or KP-NH® in combination with a Biotage autopurifier system (SP4or Isolera Four®) and eluents such as gradients of hexane/ethyl acetateor DCM/methanol. In some cases, the compounds may be purified bypreparative HPLC using for example a Waters autopurifier equipped with adiode array detector and/or on-line electrospray ionization massspectrometer in combination with a suitable prepacked reverse phasecolumn and eluents such as gradients of water and acetonitrile which maycontain additives such as trifluoroacetic acid, formic acid or aqueousammonia.

In some cases, purification methods as described above can provide thosecompounds of the present invention which possess a sufficiently basic oracidic functionality in the form of a salt, such as, in the case of acompound of the present invention which is sufficiently basic, atrifluoroacetate or formate salt for example, or, in the case of acompound of the present invention which is sufficiently acidic, anammonium salt for example. A salt of this type can either be transformedinto its free base or free acid form, respectively, by various methodsknown to the person skilled in the art, or be used as salts insubsequent biological assays. It is to be understood that the specificform (e.g. salt, free base etc.) of a compound of the present inventionas isolated and as described herein is not necessarily the only form inwhich said compound can be applied to a biological assay in order toquantify the specific biological activity.

In the case of the synthesis intermediates and working examples of theinvention described hereinafter, any compound specified in the form of asalt of the corresponding base or acid is generally a salt of unknownexact stoichiometric composition, as obtained by the respectivepreparation and/or purification process. Unless specified in moredetail, additions to names and structural formulae, such as“hydrochloride”, “trifluoroacetate”, “sodium salt” or “x HCl”, “xCF₃COOH”, “x Na⁺” should not therefore be understood in a stoichiometricsense in the case of such salts, but have merely descriptive characterwith regard to the salt-forming components present therein.

This applies correspondingly if synthesis intermediates or workingexamples or salts thereof were obtained in the form of solvates, forexample hydrates, of unknown stoichiometric composition (if they are ofa defined type) by the preparation and/or purification processesdescribed.

HPLC and LC-MS Methods:

Method 1 (LC-MS)

Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLCHSS T3 1.8 50×1 mm; eluent A: 1 l water+0.25 ml 99% formic acid, eluentB: 1 l acetonitrile+0.25 ml 99% formic acid; gradient: 0.0 min 90% A→1.2min 5% A→2.0 min 5% A; oven: 50° C.; flow rate: 0.40 ml/min; UVdetection: 208-400 nm.

Method 2 (LC-MS)

Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity UPLCHSS T3 1.8 50×1 mm; eluent A: 1 l water+0.25 ml 99% formic acid, EluentB: 1 l acetonitrile+0.25 ml 99% formic acid; gradient: 0.0 min 95% A→6.0min 5% A→7.5 min 5% A; oven: 50° C.; flow rate: 0.35 ml/min; UVdetection: 210-400 nm.

Method 3 (LC-MS)

Instrument MS: Thermo Scientific FT-MS; Instrument type UHPLC+: ThermoScientific UltiMate 3000; Column: Waters, HSST3, 2.1×75 mm, C18 1.8 μm;eluent A: 1 l water+0.01% formic acid; eluent B: 1 l acetonitrile+0.01%formic acid; gradient: 0.0 min 10% B→2.5 min 95% B→3.5 min 95% B; oven:50° C.; flow rate: 0.90 ml/min; UV detection: 210 nm/optimum integrationpath 210-300 nm.

Method 4 (Preparative HPLC)

Column: Chromatorex or Reprosil C18 10 μm; 125×30 mm, eluent A:water+0.1% formic acid, eluent B: acetonitrile+0.1% formic acid;gradient: 3 min 10% B, 17.5 min 95% B, 19.5 min 100% B, 20 min 10% B;flow rate: 75 ml/min, run time: 20 min, detection at 210 nm.

Method 5: (LC-MS)

Instrument: Agilent MS Quad 6150;HPLC: Agilent 1290; Column: WatersAcquity UPLC HSS T3 1.8μ50×2.1 mm; eluent A: 1 l water+0.25 ml 99%formic acid, eluent B: 1 l acetonitrile+0.25 ml 99% formic acid;gradient: 0.0 min 90% A→0.3 min 90% A→1.7 min 5% A→3.0 min 5% A; oven:50° C.; flow rate: 1.20 ml/min; UV detection: 205-305 nm.

Method 6 (LC-MS)

Instrument MS: Waters (Micromass) Quattro Micro; Instrument Waters UPLCAcquity; Column: Waters BEH C18 1.7μ 50×2.1 mm; eluent A: 1 l water+0.01mol ammonium formiat, eluent B: 1 l acetonitrile; gradient: 0.0 min 95%A, 0.1 min 95% A, 2.0 min 15% A, 2.5 min 15% A, 2.51 min 10% A, 3.0 min10% A; oven: 40° C.; flow rate: 0.5 ml/min; UV detection: 210 nm.

Microwave: The microwave reactor used was an Initiator⁺ microwave systemwith robot sixty from Biotage®.

EXPERIMENTAL SECTION—STARTING MATERIALS AND INTERMEDIATES Example 1A{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetonitrile

In a 2 l reaction vessel, 100 g (273 mmol) of{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}aceticacid (synthesis described as Example 8A in WO 2010/105770-A1), 43.3 g(547 mmol) of pyridine and 33 mg (0.3 mmol) of 4-dimethylaminopyridinewere dissolved in 300 ml THF. The resulting solution was treated at 5°C. with 52.8 g (438 mmol) of 2,2-dimethylpropanoylchloride over 15minutes and the resulting mixture was stirred at room temperature for2.5 hours. After cooling to 0° C., 183 ml of 28% aqueous ammoniasolution was added over 1 h while the solution temperature was keptbetween 10° C. and 20° C. and at the resulting mixture then stirred at5° C. for an additional time period of 1 h. 500 ml methyltert-butylether and 300 ml 20% aqueous citric acid were then added whilekeeping the internal temperature between 10° C. and 20° C. The phaseswere the separated and the organic phase was washed with 300 ml of 20%aqueous citric acid followed by 300 ml saturated aqueous sodiumhydrogencarbonate solution and finally with 300 ml of 10% aqueous sodiumchloride solution. The organic phase was evaporated at 60° C. underreduced pressure until an oily residue was obtained. 300 ml THF was thenadded and the solution was evaporated again until an oily solution wasobtained. This operation was repeated a second time. The oil residue wasretaken in 360 ml THF and treated with 172 g (820 mmol) trifluoroaceticacid anhydride over 20 min at a temperature between 10° C. and 20° C.The resulting solution was then stirred at room temperature for 1 h. 720ml 4-methyl-2-pentanone and 650 ml 7.5% aqueous sodium hydroxidesolution were added at a temperature between 10° C. and 20° C. Finallythe pH-value was adjusted to pH=9.5 using 7.5% aqueous sodium hydroxidesolution. After phase separation, the organic phase was washed twicewith 450 ml 10% aqueous sodium chloride solution. The organic phase wasevaporated at a temperature of 80° C. under reduced pressure while 1200ml n-heptane was added.

The formed suspension was cooled to 20° C. and a solid formed which wasfiltered off and washed with 200 ml n-heptane and then dried underreduced pressure (50° C., 30 mbar) affording 88 g (93% of th.) of{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetonitrileas a solid.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.78 (d, 2H), 7.55 (d, 2H), 6.91 (d,1H), 5.17 (s, 2H), 4.34-4.23 (m, 1H), 3.98 (dd, 1H), 3.81 (dd, 1H).

Example 2A Methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate

In a 4 l reaction vessel, 200 g (576.9 mmol) of{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetonitrile(Example 1 A) in 1600 ml methanol was treated with 5.2 g (28 mmol)sodium methanolate (30% in methanol) and the resulting mixture wasstirred at 50° C. for 2.5 hours. The solution was then evaporated at 50°C. under reduced pressure until an oily solution was obtained. 2000 mlmethyl tert-butylether was added and the solution was concentrated untila volume of 800 ml was achieved. 3000 ml n-heptane was then added and asuspension was formed. After cooling at 20° C., the solid was filteredand washed with 500 ml n-heptane and then dried under reduced pressure(50° C., 30 mbar) affording 175 g (80% of th.) of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidateas a solid.

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.01 (s, 1H), 7.78 (d, 2H), 7.62 (d,2H), 6.93 (br. s, 1H), 4.50 (s, 2H), 4.35-4.23 (m, 1H), 3.96 (dd, 1H),3.81 (dd, 1H), 3.67 (s, 3H).

Example 3A Methyl3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(3-chloropyridin-2-yl)-1H-1,2,4-triazole-5-carboxylate

A solution of 150 mg of methyl2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluor-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A, 26.4 mmol) in 3 ml THF was cooled to 0° C. and then treatedwith 58.2 mg (0.48 mmol) methyl chlorooxoacetate and 275 μl (1.58 mmol)N,N-diisopropylethylamine. The resulting mixture was warmed up to roomtemperature and stirred for 1 h and cooled again to 0° C. 62.6 mg (0.436mmol) 3-chloro-2-hydrazinopyridine were then added and the reactionmixture was warmed up to room temperature and then stirred for 1 h,followed by 1 h at 120° C. in a sealed vial under microwave irradiation.The crude product was purified by preparative HPLC (Method 4).Lyophilisation of the product containing fractions afforded 25.3 mg (11%of th.) of the title compound.

LC-MS (Method 3): R_(t)=1.82 min; MS (ESIpos): m/z=558.1[M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 8.70-8.24 (m, 2H), 7.89-7.56 (m, 5H),6.92 (d, 1H), 5.22 (s, 2H), 4.46-4.20 (m, 1H), 3.79 (s, 5H).

Example 4A5-(4-Chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-(3-chloropyridin-2-yl)-1H-1,2,4-triazole-5-carboxylate(Example 3A, 13.5 g, 24.3 mmol) in tetrahydrofuran (500 ml) was treatedwith sodium hydroxide solution (5M, 65.0 ml, 325 mmol) and the resultingmixture was stirred 10 min at room temperature. The reaction mixture wasbrought to pH=1 with 1M aqueous hydrogen chloride solution and stirred10 min at room temperature. The reaction mixture was then neutralizedwith a saturated sodium hydrogen carbonate solution and thetetrahydrofuran was evaporated. The residue was diluted with water andextracted three times with ethyl acetate. The combined organic layerswere washed with a saturated sodium chloride solution and evaporated12.9 g (quant.) of the title compound which was used as such withoutfurther purification.

LC-MS (Method 1): R_(t)=0.91 min; MS (ESIpos): m/z=500.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.07 (s, 1H), 8.59 (dd, 1H), 8.30(dd, 1H), 7.96-7.47 (m, 5H), 6.92 (d, 1H), 5.33-4.98 (m, 2H), 4.45-4.19(m, 1H), 4.11-3.71 (m, 2H).

Example 5A5-(4-Chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-(3,3,3-trifluoro-2-oxopropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(Ketone Form) or5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-(3,3,3-trifluoro-2,2-dihydroxypropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(Hydrate Form)

At 0° C., a solution of5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 4A, 10.0 g, 20.0 mmol) in dichloromethane (217 ml) was treatedwith Dess-Martin periodinane (33.9 g, 80.0 mmol) and water (396 μl). Theresulting mixture was stirred 30 min at 0° C., 1 h at room temperatureand quenched with a saturated solution of sodium thiosulfate (20 ml) anda saturated solution of sodium hydrogen carbonate (20 ml) and dilutedwith ethyl acetate. After stirring 10 min at room temperature, the whitesolid was filtered off. The organic phase of the filtrate was separatedand the aqueous phase was extracted three times with ethyl acetate. Thecombined organic layers were evaporated and purified by flashchromatography (silica gel, ethyl acetate/methanol gradient) affording9.8 g (98% of th.) of the title compound

LC-MS (Method 1): R_(t)=0.91 min; MS (ESIpos): m/z=498.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.07 (s, 1H), 8.59 (dd, 1H), 8.30(dd, 1H), 7.81-7.36 (m, 7H), 5.17 (s, 2H), 4.06 (s, 1H), as monohydrate.

Example 6A tert-Butyl2-({3-[3-(4-chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}carbamoyl)pyrrolidine-1-carboxylate(Diastereomeric Mixture)

A solution of 1-(tert-butoxycarbonyl)-proline (64.7 mg, 300 μmol) inN,N-dimethylformamide (1.2 ml) was treated with HATU (114 mg, 300 μmol)and the resulting mixture was stirred 30 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloro-pyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 100 mg, 200 μmol) was then added followed byN,N-diisopropylethylamine (105 μl, 600 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. The residue waspurified by preparative HPLC (Method 4) affording 108 mg (77% of th.) ofthe title compound as a mixture of diastereomers.

LC-MS (Method 3): R_(t)=1.96 min; MS (ESIpos): m/z=696.2 [M+H]⁺(diastereomer 1)

LC-MS (Method 3): R_(t)=2.00 min; MS (ESIpos): m/z=696.2 [M+H]⁺(diastereomer 2)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.05 (s, 1H), 8.79-8.44 (m, 2H), 8.29(dd, 1H), 7.75-7.57 (m, 5H), 5.23-5.02 (m, 2H), 4.96-4.44 (m, 1H),4.37-3.90 (m, 3H), 3.56-3.05 (m, 2H, overlapping with HDO peak),2.34-1.16 (m, 13H).

Example 7A tert-Butyl2-({3-[3-(4-chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}carbamoyl)-4-fluoropyrrolidine-1-carboxylate(Diastereomeric Mixture Cis Configured)

A solution of 1-(tert-butoxycarbonyl)-4-fluoro-proline (70.1 mg, 300μmol, cis configured) in N,N-dimethylformamide (1.2 ml) was treated withHATU (114 mg, 300 μmol) and the resulting mixture was stirred 30 min atroom temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 100 mg, 200 μmol) was then added followed byN,N-diisopropylethylamine (100 μl, 600 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated.

The residue was purified by preparative HPLC (Method 4) affording 107 mg(75% of th.) of the title compound as a mixture of diastereomers.

LC-MS (Method 3): R_(t)=1.90 min; MS (ESIpos): m/z=714.2 [M+H]⁺(diastereomer 1)

LC-MS (Method 3): R_(t)=1.94 min; MS (ESIpos): m/z=714.2 [M+H]⁺(diastereomer 2)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.05 (d, 1H), 8.74-8.38 (m, 2H), 8.29(dd, 1H), 7.77-7.56 (m, 5H), 5.32-4.96 (m, 3H), 4.96-4.49 (br m, 1H),4.42-4.11 (m, 2H), 4.08-3.82 (m, 1H), 3.69-3.44 (m, 2H), 2.50-2.24 (m,1H, overlapping with DMSO peak), 2.17-1.91 (m, 1H), 1.53-1.19 (m, 9H).

Example 8A tert-Butyl2-({3-[3-(4-chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}carbamoyl)-4-fluoropyrrolidine-1-carboxylate(Diastereomeric Mixture Trans Configured)

A solution of 1-(tert-butoxycarbonyl)-4-fluoro-proline (70.1 mg, 300μmol, trans configured) in N,N-dimethylformamide (1.2 ml) was treatedwith HATU (114 mg, 300 μmol) and stirred 30 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloro-pyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 100 mg, 200 μmol) was then added followed byN,N-diisopropylethylamine (100 μl, 600 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. The residue waspurified by preparative HPLC (Method 4) affording 110 mg (76% of th.) ofthe title compound as a mixture of diastereomers.

LC-MS (Method 3): R_(t)=1.96 min; MS (ESIpos): m/z=714.2 [M+H]⁺(diastereomer 1)

LC-MS (Method 3): R_(t)=2.01 min; MS (ESIpos): m/z=714.2 [M+H]⁺(diastereomer 2)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.11-8.99 (m, 1H), 8.99-8.61 (br m,1H), 8.61-8.55 (m, 1H), 8.34-8.26 (m, 1H), 7.74-7.57 (m, 5H), 5.40-5.04(m, 3H), 4.93-4.51 (m, 1H), 4.37-3.92 (m, 3H), 3.82-3.53 (m, 1H),3.44-3.22 (m, 1H, overlapping with HDO peak), 2.50-2.21 (m, 1H,overlapping with DMSO peak), 1.90-1.65 (m, 1H), 1.51-1.18 (m, 9H).

Example 9A tert-Butyl2-({3-[3-(4-chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}carbamoyl)-4-(trifluoromethyl)pyrrolidine-1-carboxylate(Diastereomeric Mixture Cis Configured)

A solution of 1-(tert-butoxycarbonyl)-4-(trifluoromethyl)-proline (85.1mg, 300 μmol, cis configured) in N,N-dimethylformamide (1.2 ml) wastreated with HATU (114 mg, 300 μmol) and stirred 30 min at roomtemperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 100 mg, 200 μmol) was then added followed byN,N-diisopropylethylamine (100 μl, 600 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. The residue waspurified by preparative HPLC (Method 4) affording 116 mg (76% of th.) ofthe title compound as a mixture of diastereomers.

LC-MS (Method 3): R_(t)=2.11 min; MS (ESIpos): m/z=764.2 [M+H]⁺(diastereomer 1)

LC-MS (Method 3): R_(t)=2.14 min; MS (ESIpos): m/z=764.2 [M+H]⁺(diastereomer 2)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.21-8.65 (m, 2H), 8.58 (dt, 1H),8.29 (dt, 1H), 7.80-7.54 (m, 5H), 5.19-4.92 (m, 2H), 4.91-4.50 (m, 1H),4.43-3.93 (m, 3H), 3.86-3.67 (m, 1H), 3.42-3.07 (m, 1H, overlapping withHDO peak), 2.83-2.21 (m, 1H, overlapping with DMSO peak), 2.00-1.46 (m,1H), 1.46-1.21 (m, 10H).

Example 10A tert-Butyl2-({3-[3-(4-chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}carbamoyl)-4,4-difluoropyrrolidine-1-carboxylate(Diastereomeric Mixture)

A solution of 1-(tert-butoxycarbonyl)-4,4-difluoro-proline (75.5 mg, 300μmol) in N,N-dimethylformamide (1.2 ml) was treated with HATU (114 mg,300 μmol) and stirred 30 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 100 mg, 200 μmol) was then added followed byN,N-diisopropylethylamine (100 μl, 600 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. The residue waspurified by preparative HPLC (Method 4) affording 104 mg (71% of th.) ofthe title compound as a mixture of diastereomers.

LC-MS (Method 3): R_(t)=2.04 min; MS (ESIpos): m/z=732.2 [M+H]⁺(diastereomer 1)

LC-MS (Method 3): R_(t)=2.07 min; MS (ESIpos): m/z=732.2 [M+H]⁺(diastereomer 2)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.14-8.69 (m, 2H), 8.58 (dd, 1H),8.29 (dt, 1H), 7.75-7.55 (m, 5H), 5.22-5.00 (m, 2H), 4.95-4.51 (br m,1H), 4.41-4.15 (m, 2H), 4.10-3.92 (br m, 1H), 3.85-3.58 (m, 2H),2.96-2.60 (m, 1H), 2.27-2.01 (m, 1H), 1.52-1.16 (m, 9H).

Example 11A4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Racemate)

A suspension of5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-4-(3,3,3-trifluoro-2-oxopropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 5A, 9.82 g, 19.7 mmol) in toluene (78 ml, 730 mmol) was treatedwith p-toluensulfonic acid mono hydrate (1.87 g, 9.85 mmol) and1-phenylmethanamine (3.9 ml, 35 mmol) and heated 2 h at 110° C. in aclosed vessel. Triethylamine (8.2 ml, 59 mmol) was then added and theresulting mixture was heated 34 h at 110° C. under microwaveirradiation. The reaction mixture was then diluted with methyltert-butyl ether and washed with water. The organic layer was dried overmagnesium sulfate and evaporated. The residue was retaken in methanol(380 ml, 9.3 mol), cooled to 0° C., treated with an aqueous solution ofhydrogen chloride (22 ml, 1.0 M, 22 mmol) and stirred at roomtemperature for 30 min. An aqueous solution of hydrogen chloride (20 ml,1.0 M, 20 mmol) was then added at 0° C. and the resulting mixture wasstirred 72 h at room temperature. The reaction mixture was brought topH=9 with a saturated solution of hydrogen carbonate and evaporated. Theresidue was purified by flash chromatography (silica gel, ethylacetate/methanol) afforded 4.5 g (38% of th.) of the title compound.

LC-MS (Method 1): R_(t)=0.84 min; MS (ESIpos): m/z=499.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.06 (s, 1H), 8.58 (dd, 1H), 8.29(dd, 1H), 7.86-7.51 (m, 5H), 5.14 (s, 2H), 4.02 (dd, 1H), 3.79 (dd, 1H),3.60-3.40 (m, 1H), 2.09 (d, 2H).

The two enantiomers were separated by preparative chiral HPLC [samplepreparation: 101 mg dissolved in 12 ml warmethanol/acetonitrile/methanol mixture; injection volume: 350 μl; column:Daicel Chiralpak IC 5 m, 250×20 mm; eluent: iso-hexane/2-propanol 50:50;flow rate: 20 ml/min; temperature: 23° C.; UV detection: 220 nm]. Afterseparation, 34 mg of enantiomer 1 (Example 12A), which eluted first, and36 mg of enatiomer 2 (Example 13A), which eluted later, were isolated.

Example 12A4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Enantiomer 1)

For separation conditions see Example 11A.

Analytical chiral HPLC: R_(t)=3.28 min, e.e. =99.4% [column: DaicelChiralpak IC 3 m, 50×4.6 mm; eluent: iso-hexane/ethanol 50:50+0.2%diethylamine; flow rate: 1.0 ml/min; temperature: 23° C.; UV detection:220 nm].

LC-MS (Method 3): R_(t)=1.58 min; MS (ESIpos): m/z=499.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.06 (s, 1H), 8.58 (dd, 1H), 8.29(dd, 1H), 7.78-7.54 (m, 5H), 5.14 (s, 2H), 4.02 (dd, 1H), 3.79 (dd, 1H),3.60-3.41 (m, 1H), 2.09 (d, 2H).

Example 13A4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Enantiomer 2)

For separation conditions see Example 11A.

Analytical chiral HPLC: R_(t)=3.72 min, e.e. =98.3% [column: DaicelChiralpak IC 3 μm, 50×4.6 mm; eluent: iso-hexane/ethanol 50:50+0.2%diethylamine; flow rate: 1.0 ml/min; temperature: 23° C.; UV detection:220 nm].

LC-MS (Method 3): R_(t)=1.58 min; MS (ESIpos): m/z=499.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.06 (s, 1H), 8.58 (dd, 1H), 8.29(dd, 1H), 7.77-7.56 (m, 5H), 5.14 (s, 2H), 4.02 (dd, 1H), 3.79 (dd, 1H),3.58-3.39 (m, 1H), 2.09 (d, 2H).

Example 14A Methyl3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazole-5-carboxylate

A solution of 1.0 g ofmethyl-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluor-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate(Example 2A) (2.64 mmol) in 20 ml 1,4-dioxane was cooled to 10° C. andthen treated with 388 mg (3.17 mmol) methyl chlorooxoacetate and 0.55 mL(3.18 mmol) N,N-diisopropylethylamine. The resulting mixture was thenstirred for 30 min. A prestirred solution of 1.10 g (3.17 mmol)2-hydrazino-3-(trifluoro-methyl)pyridine (4-methylbenzenesulfonate salt1:1), 0.65 mL (3.72 mmol) N,N-diisopropylethyl-amine and 506 mg (3.19mmol) anhydrous copper(II) sulfate in 10 mL 1,4-dioxane were added tothe reaction mixture and the resulting mixture was then stirredovernight at room temperature. Water was then added and the aqueousphase was extracted with ethyl acetate, the combined organic phases werewashed with aqueous sodium chloride solution, dried over magnesiumsulfate and evaporated. The residue was purified by flash chromatography(silica gel, cyclohexane/ethyl acetate 1:1) affording 777 mg (50% ofth.) of the title compound as a solid.

LC-MS (Method 1): Rt=1.00 min; MS(ESIpos): m/z=592.6 [M+H]⁺

¹H NMR (DMSO-d₆, 400 MHz): δ=8.93 (d, 1H), 8.60 (dd, 1H), 7.98 (dd, 1H),7.75 (d, 2H), 7.67-7.57 (m, 2H), 6.91 (d, 1H), 5.22 (s, 2H), 4.37-4.22(m, 1H), 4.10-3.97 (m, 1H), 3.85 (dd, 1H), 3.77 (s, 3H).

Example 15A5-(4-Chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of methyl3-({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}methyl)-1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazole-5-carboxylate(6.00 g, 10.1 mmol) in THF (90 ml) was treated with an aqueous sodiumhydroxide solution (12 ml, 5.0 M, 58 mmol) and stirred 10 min at roomtemperature. The reaction mixture was brought to pH=1 with an aqueoushydrochloric acid solution (1N) and stirred 20 min at room temperature.The reaction mixture was then brought to neutral pH with saturatedaqueous sodium hydrogencarbonate solution and THF was evaporated. Theresidue was diluted with water, the aqueous phase was extracted withethyl acetate. The combined organic layers were washed with a saturatedsodium chloride solution and evaporated affording 5.47 g (quant.) of thetitle compound.

LC-MS (Method 3): R_(t)=1.82 min; MS (ESIpos): m/z=534.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.11 (s, 1H), 8.89 (d, 1H), 8.54 (dd,1H), 7.87 (dd, 1H), 7.80-7.57 (m, 4H), 6.91 (d, 1H), 5.23-5.05 (m, 2H),4.39-4.19 (m, 1H), 4.10-3.74 (m, 2H).

Example 16A5-(4-Chlorophenyl)-2-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-(3,3,3-trifluoro-2-oxopropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(Hydrate Form)

At 0° C., a solution of5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(4.44 g, 8.32 mmol) in dichloromethane (90 ml) was treated with1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (14.1 g, 33.3mmol, Dess-Martin Periodinane), stirred 30 min at 0° C. and 1 h at roomtemperature. The reaction mixture was quenched with a saturated solutionof sodium thiosulfate (20 ml) and a saturated solution of sodiumhydrogenocarbonate (20 ml) and diluted with ethyl acetate. The resultingmixture was stirred 10 min at room temperature. The aqueous phase wasfiltered off and extracted with ethyl acetate. The combined organiclayers were evaporated.

The residue was purified by flash chromatography (silica gel,cyclohexane/ethyl acetate gradient) affording 3.57 g (66% purity, 53% ofth.) of the title compound.

LC-MS (Method 2): R_(t)=3.02 min; MS (ESIneg): m/z=532.0 [M+H]⁺ (ketoneform)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.11 (s, 1H), 8.89 (dd, 1H), 8.54(dd, 1H), 7.92-7.83 (m, 1H), 7.76-7.54 (m, 4H), 7.46 (s, 2H), 5.16 (s,2H), 4.05 (s, 2H) (hydrate form).

Example 17A4-[(2S)-2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of5-(4-chlorophenyl)-2-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-4-(3,3,3-trifluoro-2-oxopropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(720 mg, 1.35 mmol) in toluene (5.4 ml) was treated with4-toluenesulfonic acid (129 mg, 677 mol) and 1-phenylmethanamine (270μl, 2.4 mmol). The resulting mixture was stirred at 110° C. for 2 hunder microwave irradiation. Triethylamine (570 μl, 4.1 mmol) was thenadded, the resulting mixture was stirred 24 h at 110° C. under microwaveirradiation and evaporated. The residue was retaken in methanol (14 ml,330 mmol) and treated with an aqueous hydrochloric acid solution (2.8ml, 1.0 M, 2.8 mmol). The resulting mixture was stirred overnight atroom temperature, brought to pH=9 with an aqueous saturated solution ofsodium hydrogenocarbonate and evaporated. The residue was purified byflash chromatography (silica gel, ethyl acetate/methanol gradient)affording 336 mg (45% of th.) of the title compound.

LC-MS (Method 3): R_(t)=1.68 min; MS (ESIpos): m/z=533.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.11 (s, 1H), 8.89 (dd, 1H), 8.53(dd, 1H), 7.86 (dd, 1H), 7.75-7.56 (m, 4H), 5.13 (s, 2H), 4.08-3.90 (m,1H), 3.78 (dd, 1H), 3.49 (br dd, 1H), 2.09 (d, 2H).

Example 18A Tert-butyl(2R)-2-({(2S)-3-[3-(4-chlorophenyl)-5-oxo-1-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}carbamoyl)-3,3-difluoroazetidine-1-carboxylate(Diastereomeric Mixture)

A solution of 1-(tert-butoxycarbonyl)-3,3-difluoroazetidine-2-carboxylicacid (39.7 mg, 167 μmol) in DMF (400 μl) was treated with HATU (63.7 mg,167 μmol) and stirred 20 min at room temperature. A solution of4-[(2S)-2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(70.0 mg, 85% purity, 112 μmol) in DMF (400 μL) was added followed byN,N-diisopropylethylamine (58 μl, 330 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. Purification bypreparative HPLC (Method 7) afforded 69.0 mg (82% of th.) of the titlecompound.

LC-MS (Method 3): R_(t)=2.09 min; MS (ESIpos): m/z=752.2 [M+H]⁺

LC-MS (Method 3): R_(t)=2.14 min; MS (ESIpos): m/z=752.2 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 9.34-8.42 (m, 4H), 7.99-7.47 (m, 5H),5.25-4.71 (m, 4H), 4.48-3.82 (m, 4H), 1.63-0.93 (br s, 9H).

Example 19A Tert-butyl(2S,4R)-2-({(2S)-3-[3-(4-chlorophenyl)-5-oxo-1-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}carbamoyl)-4-fluoropyrrolidine-1-carboxylate(Diastereomeric Mixture)

A solution of (4R)-1-(tert-butoxycarbonyl)-4-fluoro-L-proline (39.1 mg,167 μmol) in DMF (400 μl) was treated with HATU (63.7 mg, 167 μmol) andstirred 20 min at room temperature. A solution of4-[(2S)-2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(70.0 mg, 85% purity, 112 μmol) in DMF (400 μL) was added followed byN,N-diisopropylethylamine (58 μl, 330 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. Purification bypreparative HPLC (Method 7) afforded 75.5 mg (90% of th.) of the titlecompound.

LC-MS (Method 3): R_(t)=2.04 min; MS (ESIpos): m/z=748.2 [M+H]⁺

LC-MS (Method 3): R_(t)=2.09 min; MS (ESIpos): m/z=748.2 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 9.19-8.42 (m, 4H), 7.96-7.52 (m, 5H),5.40-4.45 (m, 4H), 4.39-3.90 (m, 3H), 3.81-3.34 (m, 2H), 2.45-1.56 (m,2H), 1.48-1.15 (m, 9H).

Example 20A Tert-butyl(2S,4S)-2-({(2S)-3-[3-(4-chlorophenyl)-5-oxo-1-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}carbamoyl)-4-fluoropyrrolidine-1-carboxylate(Diastereomeric Mixture)

A solution of (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-proline (39.1 mg,167 μmol) in DMF (400 μl) was treated with HATU (63.7 mg, 167 μmol) andstirred 20 min at room temperature. A solution of4-[(2S)-2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(600 μl, 85% purity, 110 μmol) in DMF (400 μL) was added followed byN,N-diisopropylethylamine (58 μl, 330 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. Purification bypreparative HPLC (Method 7) afforded 82.0 mg (98% of th.) of the titlecompound.

LC-MS (Method 3): R_(t)=1.98 min; MS (ESIpos): m/z=748.2 [M+H]⁺

LC-MS (Method 3): R_(t)=2.02 min; MS (ESIpos): m/z=748.2 [M+H]⁺

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 9.26-8.28 (m, 4H), 8.01-7.43 (m, 5H),5.34-4.51 (m, 4H), 4.39-4.12 (m, 2H), 4.05-3.80 (m, 1H), 3.70-3.41 (m,2H), 2.45-1.91 (m, 2H), 1.52-1.09 (m, 9H).

EXPERIMENTAL SECTION—EXAMPLES Example 1N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}oxetane-3-carboxamide(Racemate)

At 0° C., a solution of oxetane-3-carboxylic acid (153 mg, 1.50 mmol) indichloromethane (4.3 ml) was treated with1-chloro-N,N,2-trimethylprop-1-en-1-amine (320 μl, 2.4 mmol) and stirred1 h at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 150 mg, 300 μmol), N,N-diisopropylethylamine (370 μl, 2.1mmol) and 4-dimethylaminopyridine (184 mg, 1.50 mmol) were added to thereaction mixture at 0° C. The resulting mixture was stirred 2 h at roomtemperature and evaporated. The residue was purified by preparative HPLC(Method 4) affording 54.1 mg (31% of th.) of the title compound.

LC-MS (Method 3): R_(t)=1.54 min; MS (ESIpos): m/z=583.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.05 (s, 1H), 8.73-8.48 (m, 2H), 8.29(dd, 1H), 7.80-7.50 (m, 5H), 5.24-5.01 (m, 2H), 4.85-4.63 (m, 1H),4.62-4.35 (m, 4H), 4.23 (dd, 1H), 4.00 (dd, 1H), 3.73-3.50 (m, 1H).

Example 2N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-trifluoropropan-2-yl}-1,1,1-trifluoropropan-2-yl}-2-oxoimidazolidine-4-carboxamide(Diastereomeric Mixture)

A solution of 2-oxoimidazolidine-4-carboxylic acid (39.1 mg, 300 μmol)in N,N-dimethylformamide (1.2 ml) was treated with HATU (114 mg, 300μmol) and stirred 30 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 100 mg, 200 μmol) was then added followed byN,N-diisopropylethylamine (100 μl, 600 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. The residue waspurified by preparative HPLC (Method 4) affording 38.8 mg (32% of th.)of the title compound as a mixture of diastereomers.

LC-MS (Method 3): R_(t)=1.37 min; MS (ESIpos): m/z=611.1 [M+H]⁺(diastereomer 1)

LC-MS (Method 3): R_(t)=1.39 min; MS (ESIpos): m/z=611.1 [M+H]⁺(diastereomer 2)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.06 (d, 1H), 8.90-8.48 (m, 2H), 8.29(d, 1H), 7.78-7.54 (m, 5H), 6.54-6.21 (m, 2H), 5.25-5.02 (m, 2H),4.89-4.58 (m, 1H), 4.39-4.19 (m, 1H), 4.02 (ddd, 2H), 3.60-3.40 (m, 1H),3.11-2.95 (m, 1H).

Example 3N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}oxetane-2-carboxamide(Diastereomeric Mixture)

At 0° C., a solution of oxetane-2-carboxylic acid (153 mg, 1.50 mmol) indichloromethane (4.3 ml) was treated with1-chloro-N,N,2-trimethylprop-1-en-1-amine (321 mg, 2.40 mmol) andstirred 2 h at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloro-pyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 150 mg, 300 μmol), N,N-diisopropylethylamine (1.9 ml, 2.1mmol) and 4-(dimethylamino)pyridine (260 μl, 1.5 mmol) were added to thereaction mixture at 0° C. The resulting mixture was stirred overnight atroom temperature and evaporated. The residue was purified by preparativeHPLC (Method 4) affording 119 mg (68% of th.) of the title compound.

LC-MS (Method 1): R_(t)=0.87 min; MS (ESIpos): m/z=583.2 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.05 (d, 1H), 8.78 (dd, 1H), 8.58(dd, 1H), 8.29 (dt, 1H), 7.79-7.51 (m, 5H), 5.26-5.02 (m, 2H), 4.98-4.72(m, 2H), 4.62-4.40 (m, 2H), 4.40-3.96 (m, 2H), 2.97-2.74 (m, 1H),2.41-2.14 (m, 1H).

Example 4N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}acetamide(Racemate)

A solution of4-[2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 80.0 mg, 160 mol) in dichloromethane (800 μl) was treatedwith N,N-diisopropylethylamine (84 μl, 480 μmol) followed by (19.6 mg,160 μmol) and acetyl chloride (17 μl, 240 μmol), stirred 1 h at roomtemperature and evaporated. The residue was purified by preparative HPLC(Method 4) affording 41.2 mg (48% of th.) of the title compound.

LC-MS (Method 1): R_(t)=0.84 min; MS (ESIpos): m/z=541.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.05 (s, 1H), 8.62-8.47 (m, 2H), 8.29(dd, 1H), 7.75-7.56 (m, 5H), 5.21-5.05 (m, 2H), 4.77-4.57 (m, 1H), 4.21(dd, 1H), 3.97 (dd, 1H), 1.72 (s, 3H).

Example 5N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-2-cyanoacetamide(Racemate)

A solution of cyanoacetic acid (16.4 mg, 192 μmol) inN,N-dimethylformamide (800 μl) was treated with HATU (73.1 mg, 192 μmol)and stirred 30 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]-methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 80.0 mg, 160 μmol) was then added followed byN,N-diisopropylethylamine (84 μl, 480 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. The residue waspurified by preparative HPLC (Method 4) affording 54.7 mg (60% of th.)of the title compound.

LC-MS (Method 1): R_(t)=0.92 min; MS (ESIpos): m/z=566.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.12-9.01 (m, 2H), 8.58 (dd, 1H),8.29 (dd, 1H), 7.74-7.57 (m, 5H), 5.23-5.07 (m, 2H), 4.78-4.58 (m, 1H),4.24 (dd, 1H), 4.00 (dd, 1H), 3.78-3.48 (m, 2H).

Example 6N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-2-methoxyacetamide(Racemate)

A solution of4-[2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 80.0 mg, 160 mol) in dichloromethane (800 μl) was treatedwith N,N-diisopropylethylamine (84 μl, 480 μmol) followed by (19.6 mg,160 μmol) and methoxyacetyl chloride (22 μl, 240 μmol), stirred 1 h atroom temperature and evaporated. The residue was purified by preparativeHPLC (Method 4) affording 59.6 mg (64% of th.) of the title compound.

LC-MS (Method 1): R_(t)=0.93 min; MS (ESIpos): m/z=571.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.05 (s, 1H), 8.64-8.46 (m, 2H), 8.29(dd, 1H), 7.73-7.56 (m, 5H), 5.21-5.05 (m, 2H), 4.92-4.74 (m, 1H), 4.31(dd, 1H), 4.15-4.00 (m, 1H), 3.77 (d, 2H), 3.21 (s, 3H).

Example 7N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-2,2-difluorocyclopropanecarboxamide(Diastereomeric Mixture)

A solution of 2,2-difluorocyclopropanecarboxylic acid (29.3 mg, 240μmol) in N,N-dimethylformamide (800 μl) was treated with HATU (91.4 mg,240 μmol) and stirred 30 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 80.0 mg, 160 μmol) was then added followed byN,N-diisopropylethylamine (84 μl, 480 μmol). The resulting mixture wasstirred 1 h at room temperature and evaporated. The residue was purifiedby preparative HPLC (Method 4) affording 81.1 mg (84% of th.) of thetitle compound as a mixture of diastereomers.

LC-MS (Method 2): R_(t)=2.93 min; MS (ESIpos): m/z=603.1 [M+H]⁺(diastereomer 1)

LC-MS (Method 2): R_(t)=2.99 min; MS (ESIpos): m/z=603.1 [M+H]⁺(diastereomer 2)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.10-8.97 (m, 2H), 8.58 (dt, 1H),8.29 (ddd, 1H), 7.73-7.56 (m, 5H), 5.21-5.03 (m, 2H), 4.82-4.68 (m, 1H),4.24 (dd, 1H), 4.01 (ddd, 1H), 2.46-2.32 (m, 1H), 1.98-1.77 (m, 2H).

Example 8N-{(3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-2-fluoroacetamide(Racemate)

A solution of4-[2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 80.0 mg, 160 μmol) in dichloromethane (800 μl) was treatedwith N,N-diisopropylethylamine (84 μl, 480 μmol) followed by (19.6 mg,160 μmol) and fluoroacetyl chloride (23.2 mg, 240 μmol), stirred 1 h atroom temperature and evaporated. The residue was purified by preparativeHPLC (Method 4) affording 73.0 mg (81% of th.) of the title compound.

LC-MS (Method 3): R_(t)=1.63 min; MS (ESIpos): m/z=559.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.05 (s, 1H), 8.92 (d, 1H), 8.58 (dd,1H), 8.29 (dd, 1H), 7.74-7.57 (m, 5H), 5.25-5.04 (m, 2H), 4.94-4.64 (m,3H), 4.31 (dd, 1H), 4.06 (dd, 1H).

Example 9N-{(3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-2,2-difluoropropanamide(Racemate)

A solution of 2,2-difluoropropanoic acid (26.5 mg, 240 μmol) inN,N-dimethylformamide (800 μl) was treated with HATU (91.4 mg, 240 μmol)and stirred 30 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]-methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 80.0 mg, 160 μmol) was then added followed byN,N-diisopropylethylamine (84 μl, 480 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. The residue waspurified by preparative HPLC (Method 4) affording 75.6 mg (80% of th.)of the title compound.

LC-MS (Method 3): R_(t)=1.82 min; MS (ESIpos): m/z=591.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.50 (d, 1H), 9.05 (s, 1H), 8.58 (dd,1H), 8.29 (dd, 1H), 7.71-7.57 (m, 5H), 5.22-5.05 (m, 2H), 4.92-4.72 (m,1H), 4.35 (dd, 1H), 4.14 (dd, 1H), 1.68 (t, 3H).

Example 10N-{(3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-2-fluoropropanamide(Diastereomeric Mixture)

A solution of 2-fluoropropanoic acid (19 μl, 240 μmol) inN,N-dimethylformamide (800 μl) was treated with HATU (91.4 mg, 240 μmol)and stirred 30 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]-methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 80.0 mg, 160 μmol) was then added followed byN,N-diisopropylethylamine (84 μl, 480 μmol). The resulting mixture wasstirred 1 h at room temperature and evaporated. The residue was purifiedby preparative HPLC (Method 4) affording 74.4 mg (81% of th.) of thetitle compound as a mixture of diastereomers.

LC-MS (Method 1): R_(t)=0.97 min; MS (ESIpos): m/z=573.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.05 (d, 1H), 8.98-8.85 (m, 1H), 8.58(dt, 1H), 8.29 (dt, 1H), 7.74-7.56 (m, 5H), 5.24-4.68 (m, 4H), 4.32 (dt,1H), 4.17-4.00 (m, 1H), 1.47-1.14 (m, 3H).

Example 11N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-3,3,3-trifluoropropanamide(Racemate)

A solution of4-[2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 80.0 mg, 160 μmol) in dichloromethane (800 μl) was treatedwith N,N-diisopropylethylamine (84 μl, 480 μmol) followed byN,N-dimethylaminopyridine (19.6 mg, 160 μmol) and3,3,3-trifluoropropanoyl chloride (35.2 mg, 240 μmol), stirred overnightat room temperature and evaporated. The residue was purified bypreparative HPLC (Method 4) affording 50.0 mg (49% of th.) of the titlecompound.

LC-MS (Method 3): R_(t)=1.81 min; MS (ESIpos): m/z=609.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.07-9.02 (m, 2H), 8.58 (dd, 1H),8.29 (dd, 1H), 7.80-7.53 (m, 5H), 5.12 (d, 2H), 4.82-4.58 (m, 1H), 4.25(dd, 1H), 4.00 (dd, 1H), 3.31-3.10 (m, 3H).

Example 12N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-2-fluorocyclopropanecarboxamide(Diastereomeric Mixture)

A solution of4-[2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 80.0 mg, 160 mol) in dichloromethane (800 μl) was treatedwith N,N-diisopropylethylamine (84 μl, 480 μmol) followed byN,N-dimethylaminopyridine (19.6 mg, 160 μmol) and2-fluorocyclopropanecarbonyl chloride (29.4 mg, 240 μmol), stirredovernight at room temperature. Additional 2-fluorocyclopropanecarbonylchloride (58.9 mg, 481 μmol) were added and stirred overnight at roomtemperature. Additional 2-fluorocyclopropanecarbonyl chloride (58.9 mg,481 μmol) were added, stirred overnight at room temperature andevaporated. The residue was purified by preparative HPLC (Method 4)affording 31.3 mg (33% of th.) of the title compound as a mixture ofdiastereomers.

LC-MS (Method 1): R_(t)=0.89 min; MS (ESIpos): m/z=585.2 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.04 (d, 1H), 8.86-8.70 (m, 1H), 8.58(dt, 1H), 8.29 (dt, 1H), 7.74-7.51 (m, 5H), 5.24-4.99 (m, 2H), 4.96-4.64(m, 2H), 4.23 (dt, 1H), 4.09-3.91 (m, 1H), 1.84-1.36 (m, 2H), 1.13-0.93(m, 1H).

Example 13N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}propanamide(Racemate)

A solution of4-[2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 80.0 mg, 160 μmol) in dichloromethane (800 μl) was treatedwith N,N-diisopropylethylamine (84 μl, 480 μmol) followed byN,N-dimethylaminopyridine (19.6 mg, 160 μmol) and propanoyl chloride (21μl, 240 μmol), stirred 1 h at room temperature and evaporated. Theresidue was purified by preparative HPLC (Method 4) affording 55.1 mg(62% of th.) of the title compound.

LC-MS (Method 3): R_(t)=1.67 min; MS (ESIpos): m/z=555.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.05 (s, 1H), 8.58 (dd, 1H), 8.44 (d,1H), 8.29 (dd, 1H), 7.77-7.54 (m, 5H), 5.29-4.97 (m, 2H), 4.81-4.55 (m,1H), 4.22 (dd, 1H), 3.98 (dd, 1H), 2.11-1.87 (m, 2H), 0.87 (t, 3H).

Example 14N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}cyclopropanecarboxamide(Racemate)

A solution of cyclopropanecarboxylic acid (19 μl, 240 μmol) inN,N-dimethylformamide (800 μl) was treated with HATU (91.4 mg, 240 μmol)and stirred 15 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]-methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 80.0 mg, 160 μmol) was then added followed byN,N-diisopropylethylamine (84 μl, 480 μmol). The resulting mixture wasstirred 1 h at room temperature and evaporated. The residue was purifiedby preparative HPLC (Method 4) affording 75.6 mg (83% of th.) of thetitle compound.

LC-MS (Method 3): R_(t)=1.69 min; MS (ESIpos): m/z=567.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.05 (s, 1H), 8.79-8.48 (m, 2H), 8.29(dd, 1H), 7.79-7.45 (m, 5H), 5.25-4.98 (m, 2H), 4.86-4.60 (m, 1H), 4.21(dd, 1H), 3.98 (dd, 1H), 1.57-1.31 (m, 1H), 0.84-0.52 (m, 4H).

Example 15N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-3,3-difluorocyclobutanecarboxamide(Racemate)

A solution of 3,3-difluorocyclobutanecarboxylic acid (32.7 mg, 240 μmol)in N,N-dimethylformamide (800 μl) was treated with HATU (91.4 mg, 240μmol) and stirred 15 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 80.0 mg, 160 μmol) was then added followed byN,N-diisopropylethylamine (84 μl, 480 μmol). The resulting mixture wasstirred 1 h at room temperature and evaporated. The residue was purifiedby preparative HPLC (Method 4) affording 79.3 mg (80% of th.) of thetitle compound.

LC-MS (Method 3): R_(t)=1.86 min; MS (ESIpos): m/z=617.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.04 (s, 1H), 8.77 (d, 1H), 8.58 (dd,1H), 8.29 (dd, 1H), 7.77-7.50 (m, 5H), 5.22-5.02 (m, 2H), 4.83-4.56 (m,1H), 4.24 (dd, 1H), 4.01 (dd, 1H), 3.01-2.53 (m, 5H, overlapping withDMSO peak).

Example 161-({3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}amino)-2-methyl-1-oxopropan-2-ylacetate (Racemate)

A solution of4-[2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 80.0 mg, 160 μmol) in dichloromethane (800 μl) was treatedwith N,N-diisopropylethylamine (84 μl, 480 μmol) followed byN,N-dimethylaminopyridine (19.6 mg, 160 μmol) and1-chloro-2-methyl-1-oxopropan-2-yl acetate (34 μl, 240 μmol), stirred 1h at room temperature and evaporated. The residue was purified bypreparative HPLC (Method 4) affording 70.4 mg (70% of th.) of the titlecompound.

LC-MS (Method 1): R_(t)=0.96 min; MS (ESIpos): m/z=627.2 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.05 (s, 1H), 8.58 (dd, 1H), 8.44 (d,1H), 8.29 (dd, 1H), 7.78-7.53 (m, 5H), 5.27-4.99 (m, 2H), 4.84-4.59 (m,1H), 4.28 (dd, 1H), 4.07 (dd, 1H), 1.98 (s, 3H), 1.35 (s, 6H).

Example 17N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-2-hydroxy-2-methylpropanamide(Racemate)

A solution of1-({3-[3-(4-chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}amino)-2-methyl-1-oxopropan-2-ylacetate (Example 16) (70.4 mg, 112 μmol) in methanol (1 ml) was treatedwith sodium methoxide (6.06 mg, 112 μmol), stirred 2 h at roomtemperature and evaporated. The residue was purified by preparative HPLC(Method 4) affording 44.6 mg (68% of th.) of the title compound.

LC-MS (Method 3): R_(t)=1.65 min; MS (ESIpos): m/z=585.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.05 (s, 1H), 8.58 (dd, 1H),8.38-8.09 (m, 2H), 7.78-7.52 (m, 5H), 5.45 (s, 1H), 5.24-5.02 (m, 2H),4.91-4.64 (m, 1H), 4.36 (dd, 1H), 4.08 (dd, 1H), 1.16 (d, 6H).

Example 18N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-2-(trifluoromethyl)cyclopropanecarboxamide(Diastereomeric Mixture)

A solution of 2-(trifluoromethyl)cyclopropanecarboxylic acid (37.0 mg,240 μmol) in N,N-dimethylformamide (800 μl) was treated with HATU (91.4mg, 240 μmol) and stirred 15 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 80.0 mg, 160 μmol) was then added followed byN,N-diisopropylethylamine (84 μl, 480 μmol). The resulting mixture wasstirred 1 h at room temperature and evaporated. The residue was purifiedby preparative HPLC (Method 4) affording 70.1 mg (69% of th.) of thetitle compound as a mixture of diastereomers.

LC-MS (Method 1): R_(t)=1.02 min; MS (ESIpos): m/z=635.2 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.24-8.91 (m, 2H), 8.58 (dd, 1H),8.29 (dt, 1H), 7.76-7.51 (m, 5H), 5.23-4.99 (m, 2H), 4.84-4.57 (m, 1H),4.23 (dd, 1H), 4.01 (dd, 1H), 2.24-1.86 (m, 2H), 1.30-0.97 (m, 2H).

Example 19N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-N²-(methylsulfonyl)glycinamide(Racemate)

A solution of N-(methylsulfonyl)glycine (15.8 mg, 103 μmol) inN,N-dimethylformamid N,N-dimethylformamide (340 μl) was treated withHATU (39.2 mg, 103 μmol) and stirred 15 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 34.3 mg, 68.7 μmol) was then added followed byN,N-diisopropylethylamine (36 μl, 210 μmol). The resulting mixture wasstirred 1 h at room temperature. A pre-stirred (15 min) solution ofN-(methylsulfonyl)glycine (10.5 mg, 68.7 μmol), HATU (26.1 mg, 68.7μmol) and N,N-diisopropylethylamine (60 μl, 340 μmol) inN,N-dimethylformamide (500 μl) was then added to the reaction mixtureand the resulting solution was stirred 72 h at room temperature.Purification by preparative HPLC (Method 6) affording 28.8 mg (66% ofth.) of the title compound.

LC-MS (Method 1): R_(t)=0.84 min; MS (ESIpos): m/z=634.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.05 (s, 1H), 8.74 (d, 1H), 8.58 (dd,1H), 8.29 (dd, 1H), 7.74-7.54 (m, 5H), 7.41 (t, 1H), 5.21-5.01 (m, 2H),4.87-4.62 (m, 1H), 4.26 (dd, 1H), 3.99 (dd, 1H), 3.74-3.48 (m, 2H), 2.87(s, 3H).

Example 20N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-2-(2-oxo-1,3-oxazolidin-3-yl)acetamide(Racemate)

A solution of (2-oxo-1,3-oxazolidin-3-yl)acetic acid (34.9 mg, 240 μmol)in N,N-dimethylformamide (800 μl) was treated with HATU (91.4 mg, 240μmol) and stirred 15 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 80.0 mg, 160 μmol) was then added followed byN,N-diisopropylethylamine (84 μl, 480 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. The residue waspurified by preparative HPLC (Method 4) affording 68.2 mg (68% of th.)of the title compound.

LC-MS (Method 1): R_(t)=0.83 min; MS (ESIpos): m/z=626.3 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.06 (s, 1H), 8.82 (d, 1H), 8.58 (dd,1H), 8.29 (dd, 1H), 7.76-7.55 (m, 5H), 5.23-5.04 (m, 2H), 4.83-4.63 (m,1H), 4.37-4.17 (m, 3H), 4.02 (dd, 1H), 3.87-3.61 (m, 2H), 3.47 (t, 2H).

Example 21N-{(3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-1-cyanocyclopropanecarboxamide(Racemate)

A solution of 1-cyanocyclopropanecarboxylic acid (26.7 mg, 240 μmol) inN,N-dimethylformamide (800 μl) was treated with HATU (91.4 mg, 240 μmol)and stirred 15 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 80.0 mg, 160 μmol) was then added followed byN,N-diisopropylethylamine (84 μl, 480 μmol). The resulting mixture wasstirred 1 h at room temperature and evaporated. The residue was purifiedby preparative HPLC (Method 4) affording 61.7 mg (60% of th.) of thetitle compound.

LC-MS (Method 3): R_(t)=1.75 min; MS (ESIpos): m/z=592.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.05 (s, 1H), 8.83 (d, 1H), 8.58 (dd,1H), 8.29 (dd, 1H), 7.78-7.53 (m, 5H), 5.23-5.01 (m, 2H), 4.91-4.72 (m,1H), 4.31 (dd, 1H), 4.22-3.97 (m, 1H), 1.77-1.36 (m, 4H).

Example 22N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-1-hydroxycyclopropanecarboxamide(Racemate)

A solution of 1-hydroxycyclopropanecarboxylic acid (30.7 mg, 300 μmol)in N,N-dimethylformamide (1.2 ml) was treated with HATU (114 mg, 300μmol) and stirred 35 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 100 mg, 200 μmol) was then added followed byN,N-diisopropylethylamine (100 μl, 600 μmol). After stirring 6 h at roomtemperature, a pre-stirred (15 min) solution of1-hydroxycyclopropanecarboxylic acid (20.4 mg, 200 μmol), HATU (76.2 mg,200 μmol) in N,N-dimethylformamide (500 μl, 6.5 mmol) was then added tothe reaction mixture. The resulting solution was stirred overnight atroom temperature. Purification by preparative HPLC (Method 4) affording41.4 mg (35% of th.) of the title compound.

LC-MS (Method 1): R_(t)=0.90 min; MS (ESIpos): m/z=583.2 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.06 (s, 1H), 8.68-8.46 (m, 2H), 8.29(dd, 1H), 7.76-7.55 (m, 5H), 6.27 (s, 1H), 5.25-5.04 (m, 2H), 4.99-4.75(m, 1H), 4.40 (dd, 1H), 4.08 (dd, 1H), 1.08-0.79 (m, 4H).

Example 23 tert-Butyl3-({3-[3-(4-chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}carbamoyl)pyrrolidine-1-carboxylate(Diastereomeric Mixture)

A solution of 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (51.7mg, 240 μmol) in N,N-dimethylformamide (800 μl) was treated with HATU(91.4 mg, 240 μmol) and stirred 15 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 80.0 mg, 160 μmol) was then added followed byN,N-diisopropylethylamine (84 μl, 480 μmol). The resulting mixture wasstirred 1 h at room temperature and evaporated. The residue was purifiedby preparative HPLC (Method 4) affording 75.4 mg (68% of th.) of thetitle compound as a mixture of diastereomers.

LC-MS (Method 3): R_(t)=1.96 min; MS (ESIpos): m/z=696.2 [M+H]⁺(diastereomer 1)

LC-MS (Method 3): R_(t)=1.98 min; MS (ESIpos): m/z=696.2 [M+H]⁺(diastereomer 2)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.04 (s, 1H), 8.73 (br d, 1H), 8.58(dt, 1H), 8.29 (dt, 1H), 7.79-7.56 (m, 5H), 5.29-4.97 (m, 2H), 4.78-4.53(m, 1H), 4.37-4.16 (m, 1H), 4.02 (br dd, 1H), 3.55-3.00 (m, 4H,overlapping with HDO peak), 2.93-2.74 (br m, 1H), 2.09-1.57 (m, 2H),1.47-1.27 (m, 9H).

Example 24N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}pyrrolidine-3-carboxamide(Diastereomeric Mixture)

tert-Butyl3-({3-[3-(4-chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}carbamoyl)pyrrolidine-1-carboxylate(Example 23, 80.0 mg, 115 μmol) was dissolved in a hydrogen chloridesolution (5.0 ml, 4.0 M, 20 mmol) and stirred overnight at roomtemperature. The reaction mixture was evaporated and the residuepurified by preparative HPLC (Method 4) affording 41.8 mg (61% of th.)of the title compound as a mixture of diastereomers.

LC-MS (Method 6): R_(t)=1.35 min; MS (ESIpos): m/z=596.1 [M+H]⁺(diastereomer 1)

LC-MS (Method 6): R_(t)=1.36 min; MS (ESIpos): m/z=596.1 [M+H]⁺(diastereomer 2)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.06 (s, 1H), 8.87-8.69 (m, 1H), 8.58(dd, 1H), 8.36-8.17 (m, 2H), 7.78-7.53 (m, 5H), 5.12 (d, 2H), 4.81-4.52(m, 1H), 4.37-4.15 (m, 1H), 4.10-3.88 (m, 1H), 3.12-2.70 (m, 5H,overlapping with HDO peak), 2.04-1.55 (m, 2H).

Example 25(2E)-N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-4,4,4-trifluorobut-2-enamide(Racemate)

A solution of (2E)-4,4,4-trifluorobut-2-enoic acid (42.1 mg, 300 μmol)in N,N-dimethylformamide (1.2 ml) was treated with HATU (114 mg, 300μmol) and stirred 20 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 100 mg, 200 μmol) was then added followed byN,N-diisopropylethylamine (100 μl, 600 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. The residue waspurified by preparative HPLC (Method 4) affording 84.2 mg (68% of th.)of the title compound.

LC-MS (Method 3): R_(t)=1.91 min; MS (ESIpos): m/z=621.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.19 (d, 1H), 9.02 (s, 1H), 8.58 (dd,1H), 8.29 (dd, 1H), 7.68-7.58 (m, 5H), 6.85-6.75 (m, 1H), 6.60-6.53 (m,1H), 5.18-5.07 (m, 2H), 4.82-4.70 (m, 1H), 4.29 (dd, 1H), 4.08 (dd, 1H).

Example 26 tert-Butyl[1-({3-[3-(4-chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}carbamoyl)cyclopropyl]-carbamate(Racemate)

A solution of 1-[(tert-butoxycarbonyl)amino]cyclopropanecarboxylic acid(48.4 mg, 240 μmol) in N,N-dimethylformamide (960 l1) was treated withHATU (91.4 mg, 240 μmol) and stirred 15 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloro-pyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 80.0 mg, 160 μmol) was then added followed byN,N-diisopropylethylamine (84 μl, 480 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. The residue waspurified by preparative HPLC (Method 4) affording 60.7 mg (56% of th.)of the title compound.

LC-MS (Method 3): R_(t)=1.96 min; MS (ESIpos): m/z=682.2 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.06 (s, 1H), 8.72-8.18 (m, 3H),7.77-7.49 (m, 5H), 7.41-6.76 (m, 1H), 5.13 (s, 2H), 4.99-4.70 (br m,1H), 4.48-4.23 (br m, 1H), 4.09-3.92 (br m, 1H), 1.60-0.67 (br m, 13H).

Example 271-Amino-N-{3-[3-(4-chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}cyclopropanecarboxamide(Racemate)

tert-Butyl[1-({3-[3-(4-chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}carbamoyl)cyclopropyl]-carbamate(Example 26, 55.5 mg, 81.3 μmol) was dissolved in a hydrogen chloridesolution (5.0 ml, 4.0 M, 20 mmol) and stirred overnight at roomtemperature. The reaction mixture was evaporated and the residuepurified by preparative HPLC (Method 4) affording 14.3 mg (30% of th.)of the title compound.

LC-MS (Method 3): R_(t)=1.19 min; MS (ESIpos): m/z=582.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.06 (s, 1H), 8.73-8.06 (m, 3H),7.81-7.51 (m, 5H), 5.24-5.04 (m, 2H), 4.75 (br d, 1H), 4.29 (dd, 1H),4.06 (dd, 1H), 1.32-0.85 (m, 4H), NH₂ not visible.

Example 28 tert-Butyl[1-({3-[3-(4-chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}carbamoyl)cyclobutyl]-carbamate(Racemate)

A solution of 1-[(tert-butoxycarbonyl)amino]cyclobutanecarboxylic acid(51.7 mg, 240 μmol) in N,N-dimethylformamide (960 μl) was treated withHATU (91.4 mg, 240 μmol) and stirred 45 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloro-pyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 80.0 mg, 160 μmol) was then added followed byN,N-diisopropylethylamine (84 μl, 480 μmol).

The resulting mixture was stirred overnight at room temperature andevaporated. The residue was purified by preparative HPLC (Method 4)affording 69.0 mg (62% of th.) of the title compound.

LC-MS (Method 3): R_(t)=2.02 min; MS (ESIpos): m/z=696.2 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.19-8.93 (m, 1H), 8.58 (dd, 1H),8.29 (dd, 1H), 8.20-7.97 (m, 1H), 7.78-6.82 (m, 6H), 5.11 (s, 2H), 4.81(br s, 1H), 4.41-4.16 (m, 1H), 4.00 (dd, 1H), 2.60-2.33 (m, 1H,overlapping with HDO peak), 2.26-1.57 (m, 5H), 1.45-1.11 (m, 9H).

Example 291-Amino-N-{3-[3-(4-chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}cyclobutanecarboxamide(Racemate)

tert-Butyl[1-({3-[3-(4-chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}carbamoyl)cyclobutyl]-carbamate(Example 28, 64.0 mg, 91.9 μmol) was dissolved in a hydrogen chloridesolution (5.0 ml, 4.0 M, 20 mmol) and stirred 1 h at room temperature.The reaction mixture was evaporated and the residue purified bypreparative HPLC (Method 4) affording the title compound. Secondpurification by preparative HPLC (Method 4) afforded 23.0 mg (42% ofth.) of the title compound.

LC-MS (Method 3): R_(t)=1.18 min; MS (ESIpos): m/z=596.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.05 (s, 1H), 8.58 (dd, 1H), 8.29(dd, 1H), 7.78-7.56 (m, 6H), 5.12 (d, 2H), 4.89-4.68 (m, 1H), 4.32 (dd,1H), 4.10 (dd, 1H), 2.41-2.23 (m, 2H), 2.08-1.63 (m, 4H), NH₂ notvisible.

Example 30N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}tetrahydrothiophene-3-carboxamide1,1-dioxide (Diastereomeric Mixture)

A solution of tetrahydrothiophene-3-carboxylic acid 1,1-dioxide (39.5mg, 240 μmol) in N,N-dimethylformamide (1.0 ml) was treated with HATU(91.4 mg, 240 μmol) and stirred 15 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 80.0 mg, 160 μmol) was then added followed byN,N-diisopropylethylamine (84 μl, 480 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. The residue waspurified by preparative HPLC (Method 4) affording 59.1 mg (57% of th.)of the title compound as a mixture of diastereomers.

LC-MS (Method 3): R_(t)=1.60 min; MS (ESIpos): m/z=645.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.13-8.83 (m, 2H), 8.66-8.53 (m, 1H),8.29 (dt, 1H), 7.75-7.52 (m, 5H), 5.23-5.03 (m, 2H), 4.77-4.53 (m, 1H),4.26 (td, 1H), 4.03 (ddd, 1H), 3.27-2.90 (m, 5H), 2.33-2.18 (m, 1H),2.10-1.82 (m, 1H).

Example 31N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-3,4,4-trifluorobut-3-enamide(Racemate)

A solution of 3,4,4-trifluorobut-3-enoic acid (42.1 mg, 300 μmol) inN,N-dimethylformamide (1.2 ml) was treated with HATU (114 mg, 300 μmol)and stirred 60 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 100 mg, 200 μmol) was then added followed byN,N-diisopropylethylamine (100 μl, 600 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. The residue waspurified by preparative HPLC (Method 4) affording 31.9 mg (26% of th.)of the title compound.

LC-MS (Method 3): R_(t)=1.84 min; MS (ESIpos): m/z=621.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.14-8.88 (m, 2H), 8.58 (dd, 1H),8.29 (dd, 1H), 7.77-7.55 (m, 5H), 5.12 (d, 2H), 4.84-4.60 (m, 1H), 4.25(dd, 1H), 4.01 (dd, 1H), 3.31-3.05 (m, 2H, overlapping with HDO peak).

Example 32N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-4,4,4-trifluorobutanamide(Racemate)

A solution of 4,4,4-trifluorobutanoic acid (85.4 mg, 601 μmol) inN,N-dimethylformamide (2.0 ml) was treated with HATU (228 mg, 601 μmol)and stirred 55 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]-methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 200 mg, 401 μmol) was then added followed byN,N-diisopropylethylamine (210 μl, 1.2 mmol). The resulting mixture wasstirred overnight at room temperature and evaporated. The residue waspurified by preparative HPLC (Method 4) affording 189 mg (75% of th.) ofthe title compound.

LC-MS (Method 3): R_(t)=1.86 min; MS (ESIpos): m/z=623.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.04 (s, 1H), 8.74 (d, 1H), 8.58 (dd,1H), 8.29 (dd, 1H), 7.70-7.61 (m, 5H), 5.18-5.06 (m, 2H), 4.74-4.62 (m,1H), 4.23 (dd, 1H), 3.99 (dd, 1H), 2.48-2.15 (m, 4H).

The two enantiomers were separated by preparative chiral HPLC [samplepreparation: 189 mg dissolved in 10 ml warm ethanol+1 ml acetonitrile;injection volume: 500 μl; column: Daicel Chiralcel OX—H 5 m, 250×20 mm;eluent: iso-hexane/ethanol 60:40; flow rate: 15 ml/min; temperature: 40°C.; UV detection: 220 nm]. After separation, 96 mg of enatiomer 1(Example 33), which eluted first, and 97 mg of enantiomer 2 (Example34), which eluted later, were isolated. The two fractions wereseparately purified by preparative HPLC (Method 4) affording 80 mg ofenantiomer 1 (Example 33) and 83 mg of enantiomer 2 (Example 34).

Example 33N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-4,4,4-trifluorobutanamide(Enantiomer 1)

For separation conditions see Example 32.

Analytical chiral HPLC: R_(t)=6.59 min, e.e. =100% [column: DaicelChiralcel OX-H 5 μm, 250×4.6 mm; eluent: iso-hexane/ethanol 50:50; flowrate: 1.0 ml/min; temperature: 40° C.; UV detection: 220 nm].

LC-MS (Method 1): R_(t)=0.99 min; MS (ESIpos): m/z=623.2 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.04 (s, 1H), 8.74 (d, 1H), 8.58 (dd,1H), 8.29 (dd, 1H), 7.83-7.50 (m, 5H), 5.23-4.99 (m, 2H), 4.84-4.55 (m,1H), 4.23 (dd, 1H), 3.99 (dd, 1H), 2.49-2.08 (m, 4H).

Example 34N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-4,4,4-trifluorobutanamide(Enantiomer 2)

For separation conditions see Example 32.

Analytical chiral HPLC: R_(t)=8.50 min, e.e. =100% [column: DaicelChiralcel OX-H 5 μm, 250×4.6 mm; eluent: iso-hexane/ethanol 50:50; flowrate: 1.0 ml/min; temperature: 40° C.; UV detection: 220 nm].

LC-MS (Method 1): R_(t)=0.99 min; MS (ESIpos): m/z=623.2 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.04 (s, 1H), 8.74 (d, 1H), 8.58 (dd,1H), 8.29 (dd, 1H), 7.80-7.51 (m, 5H), 5.23-4.96 (m, 2H), 4.77-4.57 (m,1H), 4.23 (dd, 1H), 3.99 (dd, 1H), 2.48-2.12 (m, 4H).

Example 35N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-5-oxo-L-prolinamide(Diastereomeric Mixture)

A solution of 5-oxo-L-proline (31.0 mg, 240 μmol) inN,N-dimethylformamide (960 μl) was treated with HATU (91.4 mg, 240 μmol)and stirred 15 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]-methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 80.0 mg, 160 μmol) was then added followed byN,N-diisopropylethylamine (84 μl, 480 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. The residue waspurified by preparative HPLC (Method 4) affording 73 mg (58% of th.) ofthe title compound as a mixture of diastereomers.

LC-MS (Method 3): R_(t)=1.44 min; MS (ESIpos): m/z=610.1 [M+H]⁺(diastereomer 1)

LC-MS (Method 3): R_(t)=1.45 min; MS (ESIpos): m/z=610.1 [M+H]⁺(diastereomer 2)

The two diastereomers were separated by preparative chiral HPLC [samplepreparation: 72 mg dissolved in 7 ml warm ethanol+4 ml dichloromethane;injection volume: 350 μl; column: Daicel Chiralpak IC 5 m, 250×20 mm;eluent: iso-hexane/ethanol 30:70; flow rate: 15 ml/min; temperature: 50°C.; UV detection: 220 nm]. After separation, 25 mg of diastereomer 1(Example 36), which eluted first, and 31 mg of diastereomer 2 (Example37), which eluted later, were isolated.

The two fractions were separately purified by preparative HPLC (Method4) affording 21 mg of diastereomer 1 (Example 36) and 25 mg ofdiastereomer 2 (Example 37).

Example 36N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-5-oxo-L-prolinamide(diastereomer 1)

For separation conditions see Example 35.

Analytical chiral HPLC: R_(t)=6.78 min, e.e. =99.5% [column: DaicelChiralpak IC 5 m, 250×4.6 mm; eluent: iso-hexane/ethanol 25:75; flowrate: 1.0 ml/min; temperature: 50° C.; UV detection: 220 nm].

LC-MS (Method 3): R_(t)=1.44 min; MS (ESIpos): m/z=610.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.06 (s, 1H), 8.72 (d, 1H), 8.58 (dd,1H), 8.29 (dd, 1H), 7.73 (br s, 1H), 7.70-7.60 (m, 5H), 5.19-5.08 (m,2H), 4.79-4.68 (m, 1H), 4.25 (dd, 1H), 4.02 (dd, 1H), 3.91 (dd, 1H),2.31-2.17 (m, 1H), 2.16-1.98 (m, 2H), 1.76-1.60 (m, 1H).

Example 37N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-5-oxo-L-prolinamide(diastereomer 2)

For separation conditions see Example 35.

Analytical chiral HPLC: R_(t)=8.44 min, e.e. =100% [column: DaicelChiralpak IC 5 m, 250×4.6 mm; eluent: iso-hexane/ethanol 25:75; flowrate: 1.0 ml/min; temperature: 50° C.; UV detection: 220 nm].

LC-MS (Method 3): R_(t)=1.42 min; MS (ESIpos): m/z=610.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.06 (s, 1H), 8.83 (d, 1H), 8.58 (dd,1H), 8.29 (dd, 1H), 7.72-7.62 (m, 6H), 5.16-5.08 (m, 2H), 4.73-4.61 (m,1H), 4.29 (dd, 1H), 4.06-3.93 (m, 2H), 2.25-2.10 (m, 1H), 2.06-1.99 (m,2H), 1.69-1.53 (m, 1H).

Example 38N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}thietane-3-carboxamide1,1-dioxide (Racemate)

A solution of thietane-3-carboxylic acid 1,1-dioxide (36.1 mg, 240 μmol)in N,N-dimethylformamide (800 μl) was treated with HATU (91.4 mg, 240μmol) and stirred 15 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 80.0 mg, 160 μmol) was then added followed byN,N-diisopropylethylamine (84 μl, 480 μmol). The resulting mixture wasstirred 1 h at room temperature and evaporated. The residue was purifiedby preparative HPLC (Method 4) affording 72.4 mg (72% of th.) of thetitle compound.

LC-MS (Method 1): R_(t)=0.91 min; MS (ESIpos): m/z=631.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.13-8.97 (m, 2H), 8.58 (dd, 1H),8.29 (dd, 1H), 7.79-7.53 (m, 5H), 5.13 (s, 2H), 4.78-4.57 (m, 1H),4.39-3.92 (m, 6H), 3.28-3.17 (m, 1H).

The two enantiomers were separated by preparative chiral HPLC [samplepreparation: 52 mg dissolved in 5 ml warm ethanol; injection volume: 500μl; column: Daicel Chiralpak AZ-H 5 m, 250×20 mm; eluent:iso-hexane/ethanol 70:30; flow rate: 15 ml/min; temperature: 25° C.; UVdetection: 220 nm]. After separation, 24 mg of enantiomer 1 (Example39), which eluted first, and 22 mg of enantiomer 2 (Example 40), whicheluted later, were isolated.

Example 39N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}thietane-3-carboxamide1,1-dioxide (Enantiomer 1)

For separation conditions see Example 38.

Analytical chiral HPLC: R_(t)=1.83 min, e.e. =100% [column: DaicelChiralpak AZ-3 3 μm, 50×4.6 mm; eluent: iso-hexane/ethanol 50:50; flowrate: 1.0 ml/min; temperature: 23° C.; UV detection: 220 nm].

LC-MS (Method 3): R_(t)=1.64 min; MS (ESIpos): m/z=631.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.18-8.92 (m, 2H), 8.58 (dd, 1H),8.29 (dd, 1H), 7.79-7.54 (m, 5H), 5.13 (s, 2H), 4.69 (br ddd, 1H),4.42-3.91 (m, 6H), 3.27-3.12 (m, 1H).

Example 40N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}thietane-3-carboxamide1,1-dioxide (Enantiomer 2)

For separation conditions see Example 38.

Analytical chiral HPLC: R_(t)=3.07 min, e.e. =100% [column: DaicelChiralpak AZ-3 3 μm, 50×4.6 mm; eluent: iso-hexane/ethanol 50:50; flowrate: 1.0 ml/min; temperature: 23° C.; UV detection: 220 nm].

LC-MS (Method 3): R_(t)=1.64 min; MS (ESIpos): m/z=631.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.16-8.91 (m, 2H), 8.58 (dd, 1H),8.29 (dd, 1H), 7.80-7.51 (m, 5H), 5.13 (s, 2H), 4.68 (br ddd, 1H),4.39-3.97 (m, 6H), 3.28-3.09 (m, 1H).

Example 41N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-1-(trifluoromethyl)cyclopropane-carboxamide(Racemate)

A solution of 1-(trifluoromethyl)cyclopropanecarboxylic acid (37.0 mg,240 μmol) in N,N-dimethylformamide (800 μl) was treated with HATU (91.4mg, 240 μmol) and stirred 15 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 80.0 mg, 160 μmol) was then added followed byN,N-diisopropylethylamine (84 μl, 480 μmol). The resulting mixture wasstirred 1 h at room temperature and evaporated. The residue was purifiedby preparative HPLC (Method 4) affording 68.1 mg (67% of th.) of thetitle compound.

LC-MS (Method 1): R_(t)=1.04 min; MS (ESIpos): m/z=635.2 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.05 (s, 1H), 8.58 (dd, 1H), 8.39 (d,1H), 8.29 (dd, 1H), 7.80-7.53 (m, 5H), 5.12 (d, 2H), 4.87-4.66 (m, 1H),4.38-4.00 (m, 2H), 1.43-1.06 (m, 4H).

The two enantiomers were separated by preparative chiral HPLC [samplepreparation: 50 mg dissolved in 1 ml ethanol and 1 ml 2-propanol;injection volume: 250 μl; column: Daicel Chiralpak ID 5 m, 250×20 mm;eluent: n-heptan/2-propanol 50:50; flow rate: 20 ml/min; temperature:23° C.; UV detection: 220 nm]. After separation, 19 mg of enantiomer 1(Example 42), which eluted first, and 18 mg of enantiomer 2 (Example43), which eluted later, were isolated.

Example 42N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-1-(trifluoromethyl)cyclopropane-carboxamide(Enantiomer 1)

For separation conditions see Example 41.

Analytical chiral HPLC: R_(t)=1.48 min, e.e. =100% [column: DaicelChiralpak ID-3 3 μm, 50×4.6 mm; eluent: iso-hexane/ethanol 50:50; flowrate: 1.0 ml/min; temperature: 23° C.; UV detection: 220 nm].

LC-MS (Method 1): R_(t)=1.07 min; MS (ESIpos): m/z=635.2 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.05 (s, 1H), 8.58 (dd, 1H), 8.39 (d,1H), 8.29 (dd, 1H), 7.74-7.55 (m, 5H), 5.12 (d, 2H), 4.83-4.71 (m, 1H),4.27 (dd, 1H), 4.08 (dd, 1H), 1.42-1.10 (m, 4H).

Example 43N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-trifluoropropan-2-yl}-1,1,1-trifluoropropan-2-yl}-1-(trifluoromethyl)cyclopropane-carboxamide(Enantiomer 2)

For separation conditions see Example 41.

Analytical chiral HPLC: R_(t)=2.00 min, e.e. =100% [column: DaicelChiralpak ID-3 3 μm, 50×4.6 mm; eluent: iso-hexane/ethanol 50:50; flowrate: 1.0 ml/min; temperature: 23° C.; UV detection: 220 nm].

LC-MS (Method 1): R_(t)=1.08 min; MS (ESIpos): m/z=635.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.05 (s, 1H), 8.58 (dd, 1H), 8.39 (d,1H), 8.29 (dd, 1H), 7.80-7.47 (m, 5H), 5.12 (d, 2H), 4.91-4.61 (m, 1H),4.38-3.96 (m, 2H), 1.37-1.11 (m, 4H).

Example 44N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-2-(methylsulfonyl)acetamide(Racemate)

A solution of (methylsulfonyl)acetic acid (33.2 mg, 240 μmol) inN,N-dimethylformamide (800 μl) was treated with HATU (91.4 mg, 240 μmol)and stirred 15 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]-methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 80.0 mg, 160 μmol) was then added followed byN,N-diisopropylethylamine (84 μl, 480 μmol). The resulting mixture wasstirred 1 h at room temperature and evaporated. The residue was purifiedby preparative HPLC (Method 4) affording 79.9 mg (81% of th.) of thetitle compound.

LC-MS (Method 3): R_(t)=1.56 min; MS (ESIpos): m/z=619.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.25-8.98 (m, 2H), 8.58 (dd, 1H),8.29 (dd, 1H), 7.78-7.57 (m, 5H), 5.12 (s, 2H), 4.81-4.60 (m, 1H), 4.26(dd, 1H), 4.14-3.92 (m, 3H), 3.05 (s, 3H).

The two enantiomers were separated by preparative chiral HPLC [samplepreparation: 55 mg dissolved in 5 ml warm 2-propanol; injection volume:500 μl; column: Daicel Chiralpak IB 5 μm, 250×20 mm; eluent:n-heptan/2-propanol 30:70; flow rate: 20 ml/min; temperature: 25° C.; UVdetection: 220 nm]. After separation, 21 mg of enantiomer 1 (Example45), which eluted first, and 20 mg of enantiomer 2 (Example 46), whicheluted later, were isolated.

Example 45N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-2-(methylsulfonyl)acetamide(Enantiomer 1)

For separation conditions see Example 44.

Analytical chiral HPLC: R_(t)=1.84 min, e.e. =100% [column: DaicelChiralpak IB-3 3 μm, 50×4.6 mm; eluent: iso-hexane/ethanol 50:50; flowrate: 1.0 ml/min; temperature: 23° C.; UV detection: 220 nm].

LC-MS (Method 3): R_(t)=1.53 min; MS (ESIpos): m/z=619.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.32-8.97 (m, 2H), 8.58 (dd, 1H),8.29 (dd, 1H), 7.79-7.55 (m, 5H), 5.12 (s, 2H), 4.84-4.62 (m, 1H), 4.26(dd, 1H), 4.15-3.91 (m, 3H), 3.05 (s, 3H).

Example 46N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-2-(methylsulfonyl)acetamide(Enantiomer 2)

For separation conditions see Example 44.

Analytical chiral HPLC: R_(t)=2.83 min, e.e. =98.9% [column: DaicelChiralpak IB-3 3 μm, 50×4.6 mm; eluent: iso-hexane/ethanol 50:50; flowrate: 1.0 ml/min; temperature: 23° C.; UV detection: 220 nm].

LC-MS (Method 3): R_(t)=1.54 min; MS (ESIpos): m/z=619.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.20-9.01 (m, 2H), 8.58 (dd, 1H),8.29 (dd, 1H), 7.77-7.54 (m, 5H), 5.28-5.00 (m, 2H), 4.85-4.63 (m, 1H),4.26 (dd, 1H), 4.14-3.89 (m, 3H), 3.05 (s, 3H).

Example 47N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-prolinamide(Diastereomeric Mixture)

tert-Butyl2-({3-[3-(4-chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}carbamoyl)pyrrolidine-1-carboxylate(Example 6A, 108 mg, 156 μmol) was dissolved in a hydrogen chloridesolution (5.0 ml, 4.0 M, 20 mmol) and stirred overnight at roomtemperature. The reaction mixture was evaporated and the residuepurified by preparative HPLC (Method 4) affording the title compound.Second purification by preparative HPLC (Method 4) afforded 72.5 mg (73%of th.) of the title compound.

LC-MS (Method 3): R_(t)=1.11 min; MS (ESIpos): m/z=596.1 [M+H]⁺(diastereomer 1)

LC-MS (Method 3): R_(t)=1.18 min; MS (ESIpos): m/z=596.1 [M+H]⁺(diastereomer 2)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.15-8.94 (m, 1H), 8.68-8.39 (m, 2H),8.37-8.24 (m, 1H), 8.17 (s, 1H), 7.78-7.52 (m, 5H), 5.26-4.98 (m, 2H),4.78-4.58 (m, 1H), 4.44-4.22 (m, 1H), 4.18-3.96 (m, 1H), 3.50 (br dd,1H, overlapping with HDO peak), 2.94-2.63 (m, 2H), 2.03-1.75 (m, 1H),1.64-1.40 (m, 3H), NH not visible.

Example 48N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-4-fluoro-prolinamide(Diastereomeric Mixture Cis Configured)

tert-Butyl2-({3-[3-(4-chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}carbamoyl)-4-fluoropyrrolidine-1-carboxylate(Example 7A, 107 mg, 150 μmol) was dissolved in a hydrogen chloridesolution (5.0 ml, 4.0 M, 20 mmol) and stirred overnight at roomtemperature. The reaction mixture was evaporated and the residuepurified by preparative HPLC (Method 4) affording 71.6 mg (78% of th.)of the title compound.

LC-MS (Method 3): R_(t)=1.14 min; MS (ESIpos): m/z=614.1 [M+H]⁺(diastereomer 1)

LC-MS (Method 3): R_(t)=1.20 min; MS (ESIpos): m/z=614.1 [M+H]⁺(diastereomer 2)

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 9.25-8.90 (m, 2H), 8.58 (dd, 1H),8.29 (ddd, 1H), 7.77-7.55 (m, 5H), 5.43-4.97 (m, 3H), 4.86-4.53 (m, 1H),4.43-4.21 (m, 1H), 4.15-3.80 (m, 2H), 3.29-2.99 (m, 2H, overlapping withHDO peak), 2.45-2.22 (m, 1H), 2.18-1.86 (m, 1H), NH₂ not visible.

Example 49N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-4-fluoro-prolinamide(Diastereomeric Mixture Trans Configured)

tert-Butyl2-({3-[3-(4-chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}carbamoyl)-4-fluoropyrrolidine-1-carboxylate(Example 8A, 10 mg, 154 μmol) was dissolved in a hydrogen chloridesolution (5.1 ml, 4.0 M, 20 mmol) and stirred overnight at roomtemperature. The reaction mixture was evaporated and the residuepurified by preparative HPLC (Method 4) affording 77.4 mg (82% of th.)of the title compound.

LC-MS (Method 2): R_(t)=1.91 min; MS (ESIpos): m/z=614.1 [M+H]⁺(diastereomer 1)

LC-MS (Method 2): R_(t)=1.98 min; MS (ESIpos): m/z=614.1 [M+H]⁺(diastereomer 2)

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 9.06 (d, 1H), 8.70-8.45 (m, 2H), 8.29(dt, 1H), 7.76-7.50 (m, 5H), 5.34-4.99 (m, 3H), 4.83-4.54 (m, 1H), 4.29(td, 1H), 4.07 (ddd, 1H), 3.81-3.61 (m, 1H), 3.18-2.92 (m, 1H),2.90-2.67 (m, 1H), 2.32-2.05 (m, 1H), 1.83-1.50 (m, 1H), NH₂ notvisible.

Example 50N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-trifluoropropan-2-yl}-1,1,1-trifluoropropan-2-yl}-4-(trifluoromethyl)-prolinamide(Diastereomeric Mixture Cis Configured)

tert-Butyl2-({3-[3-(4-chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}carbamoyl)-4-(trifluoromethyl)-pyrrolidine-1-carboxylate(Example 9A, 116 mg, 152 μmol) was dissolved in a hydrogen chloridesolution (5.0 ml, 4.0 M, 20 mmol) and stirred overnight at roomtemperature. The reaction mixture was evaporated and the residuepurified by preparative HPLC (Method 4) affording 77.3 mg (76% of th.)of the title compound as a mixture of diastereomers.

LC-MS (Method 2): R_(t)=2.19 min; MS (ESIpos): m/z=664.1 [M+H]⁺(diastereomer 1).

LC-MS (Method 2): R_(t)=2.37 min; MS (ESIpos): m/z=664.1 [M+H]⁺(diastereomer 2).

¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 9.05 (d, 1H), 8.70-8.45 (m, 2H),8.38-8.20 (m, 1H), 7.81-7.57 (m, 5H), 5.26-4.97 (m, 2H), 4.80-4.60 (m,1H), 4.43-4.24 (m, 1H), 4.06 (ddd, 1H), 3.81-3.55 (m, 1H), 3.19-3.04 (m,1H), 2.94 (br dd, 1H), 2.71 (ddd, 1H), 2.29-2.15 (m, 1H), 1.83-1.57 (m,1H), NH not visible.

Example 51N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-2-oxopyrrolidine-3-carboxamide(Diastereomeric Mixture)

A solution of 2-oxopyrrolidine-3-carboxylic acid (38.8 mg, 300 μmol) inN,N-dimethylformamide (1.2 ml) was treated with HATU (114 mg, 300 μmol)and stirred 30 min at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 100 mg, 200 μmol) was then added followed byN,N-diisopropylethylamine (100 μl, 600 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. The residue waspurified by preparative HPLC (Method 4) affording 99.1 mg (73% of th.)of the title compound as a mixture of diastereomers.

LC-MS (Method 3): R_(t)=1.42 min; MS (ESIpos): m/z=610.1 [M+H]⁺(diastereomer 1)

LC-MS (Method 3): R_(t)=1.47 min; MS (ESIpos): m/z=610.1 [M+H]⁺(diastereomer 2)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.09-9.00 (m, 1H), 8.79-8.67 (m, 1H),8.58 (dt, 1H), 8.29 (dt, 1H), 7.92-7.52 (m, 6H), 5.19-5.01 (m, 2H),4.90-4.61 (m, 1H), 4.33-4.16 (m, 1H), 4.08-3.90 (m, 1H), 3.26-2.95 (m,3H), 2.22-1.96 (m, 2H).

Example 525-Chloro-N-{3-[3-(4-chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}thiophene-2-carboxamide(Racemate)

A solution of4-[2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 100 mg, 200 mol) in dichloromethane (1.0 ml) was treatedwith N,N-diisopropylethylamine (100 μl, 600 μmol) followed by4-(dimethylamino)pyridine (24.5 mg, 200 μmol) and5-chlorothiophene-2-carbonyl chloride (54.4 mg, 300 μmol), stirred 1.5 hat room temperature and evaporated. The residue was purified byprep-HPLC (Method 4) affording 89.5 mg (69% of th.) of the titlecompound.

LC-MS (Method 3): R_(t)=2.02 min; MS (ESIpos): m/z=643.0 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.11-8.92 (m, 2H), 8.57 (dd, 1H),8.28 (dd, 1H), 7.76-7.48 (m, 6H), 7.19 (d, 1H), 5.22-5.01 (m, 2H),4.97-4.78 (m, 1H), 4.34 (dd, 1H), 4.16 (dd, 1H).

Example 53N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-4,4-difluoro-prolinamide(Diastereomeric Mixture)

tert-Butyl2-({3-[3-(4-chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}carbamoyl)-4,4-difluoro-pyrrolidine-1-carboxylate(Example 10A, 101 mg, 138 μmol) was dissolved in a hydrogen chloridesolution (5.0 ml, 4.0 M, 20 mmol) and stirred overnight at roomtemperature. The reaction mixture was evaporated and the residuepurified by preparative HPLC (Method 4) affording 77.8 mg (89% of th.)of the title compound as a mixture of diastereomers.

LC-MS (Method 3): R_(t)=1.64 min; MS (ESIpos): m/z=632.1 [M+H]⁺(diastereomer 1).

LC-MS (Method 3): R_(t)=1.67 min; MS (ESIpos): m/z=632.1 [M+H]⁺(diastereomer 2).

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.05 (d, 1H), 8.66 (dd, 1H), 8.58(dt, 1H), 8.34-8.24 (m, 1H), 7.72-7.58 (m, 5H), 5.20-5.02 (m, 2H),4.81-4.62 (m, 1H), 4.31 (dd, 1H), 4.08 (ddd, 1H), 3.85-3.71 (m, 1H),3.23-2.90 (m, 2H), 2.47-2.29 (m, 1H), 2.25-1.99 (m, 1H), NH not visible.

Example 54 tert-Butyl2-({3-[3-(4-chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}carbamoyl)-3,3-difluoro-azetidine-1-carboxylate(Diastereomeric Mixture)

At 0° C., a solution of1-(tert-butoxycarbonyl)-3,3-difluoroazetidine-2-carboxylic acid (356 mg,1.50 mmol) in dichloromethane (4.3 ml) was treated with1-chloro-N,N,2-trimethylprop-1-en-1-amine (321 mg, 2.40 mmol) andstirred 1 h at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 150 mg, 300 μmol), N,N-diisopropylethylamine (1.9 ml, 2.1mmol) and 4-(dimethylamino)pyridine (260 μl, 1.5 mmol) were added to thereaction mixture at 0° C. The resulting mixture was stirred overnight atroom temperature and evaporated. The residue was purified by preparativeHPLC (Method 4) affording 156 mg (72% of th.) of the title compound as amixture of diastereomers.

LC-MS (Method 3): R_(t)=2.01 min; MS (ESIneg): m/z=716.1 [M−H]⁻

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.23 (br d, 1H), 9.05 (s, 1H), 8.58(dd, 1H), 8.29 (dd, 1H), 7.79-7.53 (m, 5H), 5.23-4.70 (m, 4H), 4.42-4.11(m, 3H), 3.99 (br dd, 1H), 1.58-1.20 (m, 9H).

Example 55N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-3,3-difluoroazetidine-2-carboxamide(Diastereomeric Mixture)

tert-Butyl2-({3-[3-(4-chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}carbamoyl)-3,3-difluoro-azetidine-1-carboxylate(Example 54, 109 mg, 152 μmol) was dissolved in a hydrogen chloridesolution (5.0 ml, 4.0 M, 20 mmol) and stirred overnight at roomtemperature. The reaction mixture was evaporated and the residuepurified by preparative HPLC (Method 4) affording 77.9 mg (79% of th.)of the title compound as a mixture of diastereomers.

LC-MS (Method 3): R_(t)=1.66 min; MS (ESIpos): m/z=618.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.07 (s, 1H), 8.78-8.50 (m, 2H), 8.30(dd, 1H), 7.79-7.52 (m, 5H), 5.26-5.02 (m, 2H), 4.97-4.74 (m, 1H),4.67-4.49 (m, 1H), 4.35 (dd, 1H), 4.14-3.81 (m, 2H), 3.72-3.48 (m, 1H),NH₂ not visible.

Example 56 tert-Butyl2-({3-[3-(4-chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}carbamoyl)azetidine-1-carboxylate(Diastereomeric Mixture)

At 0° C., a solution of 1-(tert-butoxycarbonyl)azetidine-2-carboxylicacid (151 mg, 751 μmol) in dichloromethane (4.3 ml) was treated with1-chloro-N,N,2-trimethylprop-1-en-1-amine (100 mg, 751 μmol) and stirred1.5 h at room temperature.4-[2-Amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one(Example 11A, 150 mg, 300 μmol), N,N-diisopropylethylamine (1.9 ml, 1.2mmol) and N,N-dimethylaminopyridine (260 μl, 1.5 mmol) were added to thereaction mixture at 0° C. The resulting mixture was stirred overnight atroom temperature and evaporated. The residue was purified by preparativeHPLC (Method 4) affording 162 mg (75% of th.) of the title compound as amixture of diastereomers.

LC-MS (Method 3): R_(t)=1.95 min; MS (ESIpos): m/z=682.2 [M+H]⁺(diastereomer 1)

LC-MS (Method 3): R_(t)=1.97 min; MS (ESIpos): m/z=682.2 [M+H]⁺(diastereomer 2)

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.05 (d, 1H), 8.88-8.51 (m, 2H), 8.29(dt, 1H), 7.78-7.54 (m, 5H), 5.27-4.60 (br m, 3H), 4.50-3.52 (br m, 5H),2.41-2.15 (br m, 1H), 2.15-1.57 (br m, 1H), 1.54-1.12 (br m, 9H).

Example 57N-{3-[3-(4-Chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}azetidine-2-carboxamide(Diastereomeric Mixture)

tert-Butyl2-({3-[3-(4-chlorophenyl)-1-{[1-(3-chloropyridin-2-yl)-1H-1,2,4-triazol-3-yl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}carbamoyl)azetidine-1-carboxylate(Example 56, 109 mg, 160 μmol) was dissolved in a hydrogen chloridesolution (3.0 ml, 4.0 M, 12 mmol) and stirred 1 h at room temperature.The reaction mixture was evaporated and the residue purified bypreparative HPLC (Method 4) affording 49.0 mg (53% of th.) of the titlecompound as mixture of diastereroisomers.

LC-MS (Method 1): R_(t)=0.68 min; MS (ESIpos): m/z=582.2 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.16-8.93 (m, 1H), 8.70-8.22 (m, 3H),7.78-7.53 (m, 5H), 5.27-5.00 (m, 2H), 4.74 (br ddd, 1H), 4.47-3.95 (m,3H), 3.65-2.88 (m, 2H, overlapping with HDO peak), 2.48-2.22 (m, 1H),2.12-1.78 (m, 1H), NH not visible.

Example 58N-{3-[3-(4-Chlorophenyl)-5-oxo-1-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-1-(trifluoromethyl)cyclopropane-1-carboxamide(Racemate)

A solution of 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (1.1 ml,230 μmol) in DMF (200 μl) was treated with HATU (85.6 mg, 225 μmol) andstirred 20 min at room temperature. A solution of4-[(2S)-2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-({1-[3-(trifluoromethyl)-pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(750 μl, 0.20 M, 150 μmol) in DMF was added followed byN,N-diisopropylethylamine (78 μl, 450 μmol). The resulting mixture wasstirred overnight at room temperature. A pre-mix solution of1-(trifluoromethyl)cyclopropane-1-carboxylic acid (1.1 ml, 75 μmol) andHATU (28.5 mg, 75.0 μmol) in DMF was added and stirred 2 h at roomtemperature. N,N-diisopropylethylamine (26 μl, 150 μmol) was added andthe resulting mixture was stirred 1 h at room temperature. Evaporationand purification by preparative HPLC (Method 7) afforded 49.4 mg (49% ofth.) of the title compound.

LC-MS (Method 3): R_(t)=2.05 min; MS (ESIpos): m/z=669.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.09 (s, 1H), 8.88 (dd, 1H), 8.53(dd, 1H), 8.38 (d, 1H), 7.86 (dd, 1H), 7.64 (s, 4H), 5.12 (d, 2H),4.85-4.69 (m, 1H), 4.37-3.98 (m, 2H), 1.41-1.00 (m, 4H).

Example 59N-{3-[3-(4-Chlorophenyl)-5-oxo-1-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-4,4,4-trifluorobutanamide(Racemate)

A solution of 4,4,4-trifluorobutanoic acid (32.0 mg, 225 μmol) in DMF(250 μl) was treated with HATU (85.6 mg, 225 μmol) and stirred 20 min atroom temperature. A solution of4-[(2R)-2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-onein DMF (750 μl, 0.20 M, 150 μmol) was added followed byN,N-diisopropylethylamine (78 μl, 450 μmol). The resulting mixture wasstirred overnight at room temperature. A pre-mix solution of4,4,4-trifluorobutanoic acid (10.7 mg, 75.0 μmol) and HATU (28.5 mg,75.0 μmol) in DMF was added and stirred 2 h at room temperature.N,N-diisopropylethylamine (26 μl, 150 μmol) was added and the resultingmixture was stirred 1 h at room temperature. Evaporation andpurification by preparative HPLC (Method 7) afforded 76.2 mg (77% ofth.) of the title compound.

LC-MS (Method 3): R_(t)=1.93 min; MS (ESIpos): m/z=657.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.08 (s, 1H), 8.89 (br dd, 1H), 8.74(d, 1H), 8.55-8.52 (m, 1H), 7.86 (dd, 1H), 7.70-7.59 (m, 4H), 5.17-5.06(m, 2H), 4.77-4.60 (m, 1H), 4.22 (dd, 1H), 3.99 (dd, 1H), 2.47-2.17 (m,4H).

Example 60N-{3-[3-(4-Chlorophenyl)-5-oxo-1-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-2,2-difluoropropanamide(Racemate)

A solution of 2,2-difluoropropanoic acid (24.8 mg, 225 μmol) in DMF (250μl) was treated with HATU (85.6 mg, 225 μmol) and stirred 20 min at roomtemperature. A solution of4-[(2R)-2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-onein DMF (750 μl, 0.20 M, 150 μmol) was added followed byN,N-diisopropylethylamine (78 μl, 450 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. Purification bypreparative HPLC (Method 7) afforded 71.5 mg (76% of th.) of the titlecompound.

LC-MS (Method 3): R_(t)=1.89 min; MS (ESIpos): m/z=625.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.49 (d, 1H), 9.10 (s, 1H), 8.89 (dd,1H), 8.53 (dd, 1H), 7.86 (dd, 1H), 7.64 (s, 4H), 5.19-5.06 (m, 2H),4.90-4.74 (m, 1H), 4.34 (dd, 1H), 4.13 (dd, 1H), 1.68 (t, 3H).

Example 61N-{3-[3-(4-Chlorophenyl)-5-oxo-1-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-2-fluoroacetamide(Racemate)

A solution of fluoroacetic acid (14.0 mg, 180 μmol) in DMF (200 μl) wastreated with HATU (68.4 mg, 180 μmol) and stirred 20 min at roomtemperature. A solution of4-[(2S)-2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-onein DMF (600 μl, 0.20 M, 120 μmol) was added followed byN,N-diisopropylethylamine (63 μl, 360 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. Purification bypreparative HPLC (Method 7) afforded 63.2 mg (89% of th.) of the titlecompound.

LC-MS (Method 3): R_(t)=1.75 min; MS (ESIpos): m/z=593.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.10 (s, 1H), 8.96-8.84 (m, 2H), 8.53(dd, 1H), 7.86 (dd, 1H), 7.63 (d, 4H), 5.21-5.06 (m, 2H), 4.94-4.65 (m,3H), 4.30 (dd, 1H), 4.06 (dd, 1H).

Example 62N-{3-[3-(4-Chlorophenyl)-5-oxo-1-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-1,1-dioxo-1lambda⁶-thietane-3-carboxamide(Racemate)

A solution of 1,1-dioxo-1lambda6-thietane-3-carboxylic acid (28.7 mg,191 μmol) in DMF (400 μl) was treated with HATU (72.8 mg, 191 μmol) andstirred 20 min at room temperature. A solution of4-[(2S)-2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(80.0 mg, 85% purity, 128 μmol) in DMF (400 μl) was added followed byN,N-diisopropylethylamine (67 μl, 380 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. Purification bypreparative HPLC (Method 7) afforded 63.7 mg (75% of th.) of the titlecompound.

LC-MS (Method 3): R_(t)=1.74 min; MS (ESIpos): m/z=665.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.10-9.02 (m, 2H), 8.88 (dd, 1H),8.53 (dd, 1H), 7.86 (dd, 1H), 7.72-7.60 (m, 4H), 5.12 (s, 2H), 4.77-4.59(m, 1H), 4.37-3.95 (m, 6H), 3.29-3.16 (m, 1H).

Example 63N-{3-[3-(4-Chlorophenyl)-5-oxo-1-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-3,3-difluorocyclobutane-1-carboxamide(Racemate)

A solution of 3,3-difluorocyclobutane-1-carboxylic acid (26.1 mg, 191μmol) in DMF (400 μl) was treated with HATU (72.8 mg, 191 μmol) andstirred 30 min at room temperature. A solution of4-[(2S)-2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(80.0 mg, 85% purity, 128 μmol) in DMF (400 μl) was added followed byN,N-diisopropylethylamine (67 μl, 380 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. Purification bypreparative HPLC (Method 7) afforded 64.0 mg (77% of th.) of the titlecompound.

LC-MS (Method 3): R_(t)=1.95 min; MS (ESIpos): m/z=651.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.08 (s, 1H), 8.88 (d, 1H), 8.76 (d,1H), 8.53 (dd, 1H), 7.86 (dd, 1H), 7.65 (d, 4H), 5.11 (d, 2H), 4.78-4.61(m, 1H), 4.23 (dd, 1H), 4.00 (dd, 1H), 2.88-2.42 (m, 5H, overlap withDMSO peak).

Example 64N-{3-[3-(4-Chlorophenyl)-5-oxo-1-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-2-(methanesulfonyl)acetamide(Racemate)

A solution of (methanesulfonyl)acetic acid (26.4 mg, 191 μmol) in DMF(400 μl) was treated with HATU (72.8 mg, 191 μmol) and stirred 30 min atroom temperature. A solution of4-[(2S)-2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(80.0 mg, 85% purity, 128 μmol) in DMF (400 μl) was added followed byN,N-diisopropylethylamine (67 μl, 380 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. Purification bypreparative HPLC (Method 7) afforded 64.1 mg (77% of th.) of the titlecompound.

LC-MS (Method 1): R_(t)=0.89 min; MS (ESIpos): m/z=653.5 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.20-9.04 (m, 2H), 8.88 (dd, 1H),8.53 (dd, 1H), 7.86 (dd, 1H), 7.72-7.56 (m, 4H), 5.11 (s, 2H), 4.83-4.63(m, 1H), 4.35-4.16 (m, 1H), 4.13-3.88 (m, 3H), 3.05 (s, 3H).

Example 65N-{3-[3-(4-Chlorophenyl)-5-oxo-1-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-1-cyanocyclopropane-1-carboxamide(Racemate)

A solution of 1-cyanocyclopropane-1-carboxylic acid (21.3 mg, 191 μmol)in DMF (400 μl) was treated with HATU (72.8 mg, 191 μmol) and stirred 20min at room temperature. A solution of4-[(2S)-2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(80.0 mg, 85% purity, 128 μmol) in DMF (400 μl) was added followed byN,N-diisopropylethylamine (67 μl, 380 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. Purification bypreparative HPLC (Method 7) afforded 46.2 mg (55% of th.) of the titlecompound.

LC-MS (Method 1): R_(t)=0.99 min; MS (ESIpos): m/z=626.5 [M+H]

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.10 (s, 1H), 8.92-8.78 (m, 2H), 8.53(dd, 1H), 7.86 (dd, 1H), 7.63 (s, 4H), 5.20-5.04 (m, 2H), 4.89-4.74 (m,1H), 4.30 (dd, 1H), 4.13 (dd, 1H), 1.68-1.38 (m, 4H).

Example 66N-{3-[3-(4-Chlorophenyl)-5-oxo-1-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-2,2-difluorocyclopropane-1-carboxamide(Diastereomeric Mixture)

A solution of 2,2-difluorocyclopropane-1-carboxylic acid (20.4 mg, 167μmol) in DMF (400 μl) was treated with HATU (63.7 mg, 167 μmol) andstirred 30 min at room temperature. A solution of4-[(2S)-2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(70.0 mg, 85% purity, 112 μmol) in DMF (400 μl) was added followed byN,N-diisopropylethylamine (58 μl, 330 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. Purification bypreparative HPLC (Method 7) afforded 58.7 mg (83% of th.) of the titlecompound.

LC-MS (Method 3): R_(t)=1.87 min; MS (ESIpos): m/z=637.1 [M+H]⁺

LC-MS (Method 3): R_(t)=1.89 min; MS (ESIpos): m/z=637.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.12-8.99 (m, 2H), 8.93-8.84 (m, 1H),8.57-8.49 (m, 1H), 7.89-7.83 (m, 1H), 7.70-7.57 (m, 4H), 5.21-5.02 (m,2H), 4.79-4.65 (m, 1H), 4.23 (dd, 1H), 4.08-3.93 (m, 1H), 2.64-2.32 (m,1H, overlap with DMSO peak), 1.96-1.77 (m, 2H).

Example 67N-{3-[3-(4-Chlorophenyl)-5-oxo-1-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-3,3,3-trifluoropropanamide(Racemate)

A solution of 3,3,3-trifluoropropanoic acid (21.4 mg, 167 μmol) in DMF(400 μl) was treated with HATU (63.7 mg, 167 μmol) and stirred 30 min atroom temperature. A solution of4-[(2S)-2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(70.0 mg, 85% purity, 112 μmol) in DMF (400 μl) was added followed byN,N-diisopropylethylamine (58 μl, 330 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. Purification bypreparative HPLC (Method 7) afforded 53.2 mg (74% of th.) of the titlecompound.

LC-MS (Method 3): R_(t)=1.91 min; MS (ESIpos): m/z=643.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.09 (s, 1H), 9.08-9.02 (m, 1H),8.90-8.86 (m, 1H), 8.53 (dd, 1H), 7.86 (dd, 1H), 7.72-7.59 (m, 4H),5.17-5.06 (m, 2H), 4.79-4.63 (m, 1H), 4.24 (dd, 1H), 4.00 (dd, 1H),3.30-3.12 (m, 2H, overlap with HDO peak).

Example 68N-{3-[3-(4-Chlorophenyl)-5-oxo-1-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-2-methoxyacetamide(Racemate)

A solution of methoxyacetic acid (15.1 mg, 167 μmol) in DMF (400 μl) wastreated with HATU (63.7 mg, 167 μmol) and stirred 30 min at roomtemperature. A solution of4-[(2S)-2-amino-3,3,3-trifluoropropyl]-5-(4-chlorophenyl)-2-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(70.0 mg, 85% purity, 112 μmol) in DMF (400 μl) was added followed byN,N-diisopropylethylamine (58 μl, 330 μmol). The resulting mixture wasstirred overnight at room temperature and evaporated. Purification bypreparative HPLC (Method 7) afforded 60.9 mg (90% of th.) of the titlecompound.

LC-MS (Method 3): R_(t)=1.75 min; MS (ESIpos): m/z=605.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 9.10 (s, 1H), 8.89 (br d, 1H), 8.53(d, 2H), 7.86 (dd, 1H), 7.70-7.58 (m, 4H), 5.19-5.05 (m, 2H), 4.92-4.74(m, 1H), 4.30 (dd, 1H), 4.06 (dd, 1H), 3.84-3.71 (m, 2H), 3.22 (s, 3H).

Example 69N-{3-[3-(4-Chlorophenyl)-5-oxo-1-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-3,3-difluoroazetidine-2-carboxamideHydrochloride (Diastereomeric Mixture)

At 0° C., tert-butyl(2R)-2-({(2S)-3-[3-(4-chlorophenyl)-5-oxo-1-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-carbamoyl)-3,3-difluoroazetidine-1-carboxylate(65.2 mg, 86.7 μmol) was dissolved in a solution of hydrochloric acid indioxane (4.0 ml, 4.0 M, 16 mmol). The resulting mixture was stirred 30min at 0° C., overnight at room temperature and evaporated. Purificationby preparative HPLC (Method 7) afforded 44.1 mg (74% of th.) of thetitle compound.

LC-MS (Method 3): R_(t)=1.74 min; MS (ESIpos): m/z=652.1 [M+H]⁺

LC-MS (Method 3): R_(t)=1.78 min; MS (ESIpos): m/z=652.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 10.39-8.61 (m, 2H), 9.17-9.04 (m,1H), 8.96-8.81 (m, 1H), 8.59-8.48 (m, 1H), 7.93-7.76 (m, 1H), 7.72-7.54(m 4H), 5.45-4.99 (m, 3H), 4.96-4.80 (m, 1H), 4.59-4.41 (m, 1H),4.39-4.21 (m, 2H), 4.14-3.96 (m, 1H).

Example 70N-{3-[3-(4-Chlorophenyl)-5-oxo-1-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-4-fluoro-L-prolinamidehydrochloride (Diastereomeric Mixture)

At 0° C., tert-butyl(2S,4R)-2-({(2S)-3-[3-(4-chlorophenyl)-5-oxo-1-({1-[3-(trifluoromethyl-)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoro-propan-2-yl}carbamoyl)-4-fluoropyrrolidine-1-carboxylate(73.9 mg, 98.8 μmol) was dissolved in a solution of hydrochloric acid indioxane (4.0 ml, 4.0 M, 16 mmol). The resulting mixture was stirred 30min at 0° C., 2 h at room temperature and evaporated. Purification bypreparative HPLC (Method 7) afforded 61.0 mg (90% of th.) of the titlecompound.

LC-MS (Method 3): R_(t)=1.31 min; MS (ESIpos): m/z=648.1 [M+H]⁺

LC-MS (Method 3): R_(t)=1.34 min; MS (ESIpos): m/z=648.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 10.75-10.17 (m, 1H), 9.70-9.40 (m,1H), 9.20-8.46 (m, 4H), 7.96-7.55 (m, 5H), 5.58-5.33 (m, 1H), 5.25-5.06(m, 2H), 4.90-4.63 (m, 1H), 4.43-4.19 (m, 2H), 4.14-3.97 (m, 1H),3.68-3.41 (m, 2H), 2.73-2.49 (m, 1H, overlap with DMSO peak), 2.11-1.80(m, 1H).

Example 71N-{3-[3-(4-Chlorophenyl)-5-oxo-1-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}-4-fluoro-L-prolinamidehydrochloride (Diastereomeric Mixture)

At 0° C., tert-butyl(2S,4S)-2-({(2S)-3-[3-(4-chlorophenyl)-5-oxo-1-({1-[3-(trifluoromethyl)pyridin-2-yl]-1H-1,2,4-triazol-3-yl}methyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]-1,1,1-trifluoropropan-2-yl}carbamoyl)-4-fluoropyrrolidine-1-carboxylate(73.1 mg, 97.7 μmol) was dissolved in a solution of hydrochloric acid indioxane (4.0 ml, 4.0 M, 16 mmol). The resulting mixture was stirred 30min at 0° C., 2 h at room temperature and evaporated. Purification bypreparative HPLC (Method 7) afforded 52.7 mg (79% of th.) of the titlecompound.

LC-MS (Method 3): R_(t)=1.31 min; MS (ESIpos): m/z=648.1 [M+H]⁺

LC-MS (Method 3): R_(t)=1.37 min; MS (ESIpos): m/z=648.1 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 10.73-10.15 (m, 1H), 9.61-9.35 (m,1H), 9.23-8.80 (m, 3H), 8.63-8.40 (m, 1H), 7.92-7.79 (m, 1H), 7.75-7.53(m, 4H), 5.50-5.25 (m, 1H), 5.23-4.94 (m, 2H), 4.85-4.58 (m, 1H),4.42-4.20 (m, 2H), 4.14-3.96 (m, 1H), 3.68-3.39 (m, 2H, overlap with HDOpeak), 2.73-2.50 (m, 1H, overlap with DMSO peak), 2.28-2.10 (m, 1H).

BIOLOGICAL ASSAYS Abbreviations and Acronyms

Acc. No. accession number

AVP arginine vasopressin

B_(max) maximal ligand binding capacity

BSA bovine serum albumin

cAMP cyclic adenosine monophosphate

Cat. No. catalogue number

cDNA complementary deoxyribonucleic acid

CHO chinese hamster ovary

CRE cAMP response element

Ct cycle threshold

DMEM/F12 Dulbecco's modified Eagle's medium/Ham's F12 medium (1:1)

DNA deoxyribonucleic acid

DMSO dimethylsulfoxide

DTT dithiothreitol

EC₅₀ half-maximal effective concentration

EDTA ethylenediamine-tetraacetic acid

FAM carboxyfluorescein succinimidyl ester

f.c. final concentration

FCS fetal calf serum

HEPES 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid

IC₅₀ half-maximal inhibitory concentration

K_(d) dissociation constant

K_(i) dissociation constant of an inhibitor

mRNA messenger ribonucleic acid

PBS phosphate buffered saline

PEG polyethylene glycol

p.o. per os, peroral

RNA ribonucleic acid

RTPCR real-time polymerase chain reaction

SPA scintillation proximity assay

TAMRA carboxytetramethylrhodamine

TRIS; Tris 2-amino-2-hydroxymethylpropane-1,3-diol

Demonstration of the activity of the compounds of the present inventionmay be accomplished through in vitro, ex vivo, and in vivo assays thatare well known in the art. For example, to demonstrate the activity ofthe compounds of the present invention, the following assays may beused.

B-1. Cellular In Vitro Assay for Determining Vasopressin ReceptorActivity

The identification of agonists and antagonists of the V1a and V2vasopressin receptors from humans, rats and dogs as well as thequantification of the activity of the compounds of the invention iscarried out using recombinant cell lines. These cell lines originallyderive from a hamster's ovary epithelial cell (Chinese Hamster Ovary,CHO K1, ATCC: American Type Culture Collection, Manassas, Va. 20108,USA). The test cell lines constitutively express the human, rat or dogV1a or V2 receptors. In case of the G_(αq)-coupled V1a receptors, cellsare also stably transfected with a modified form of thecalcium-sensitive photoproteins aequorin (human and rat V1a) or obe-lin(dog V1a), which, after reconstitution with the cofactor coelenterazine,emit light when there are increases in free calcium concentrations[Rizzuto R, Simpson A W, Brini M, Pozzan T, Nature 358, 325-327 (1992);Illarionov B A, Bondar V S, Illarionova V A, Vysotski E S, Gene 153 (2),273-274 (1995)]. The resulting vasopressin receptor cells react tostimulation of the recombinantly expressed Via receptors byintracellular release of calcium ions, which can be quantified by theresulting photoprotein luminescence. The G_(s)-coupled V2 receptors arestably transfected into cell lines expressing the gene for fireflyluciferase under control of a CRE-responsible promoter. Activation of V2receptors induces the activation of the CRE-responsive promoter via cAMPincrease, thereby inducing the expression of firefly luciferase. Thelight emitted by photoproteins of V1a cell lines as well as the lightemitted by firefly luciferase of V2 cell lines corresponds to theactivation or inhibition of the respective vasopressin receptor. Thebioluminescence of the cell lines is detected using a suitableluminometer [Milligan G, Marshall F, Rees S, Trends in PharmacologicalSciences 17, 235-237 (1996)].

Test Procedure:

Vasopressin V1a Receptor Cell Lines:

On the day before the assay, the cells are plated out in culture medium(DMEM/F12, 2% FCS, 2 mM glutamine, 10 mM HEPES, 5 μg/ml coelenterazine)in 384-well microtiter plates and kept in a cell incubator (96%humidity, 5% v/v CO₂, 37° C.). On the day of the assay, test compoundsin various concentrations are placed for 10 minutes in the wells of themicrotiter plate before the agonist [Arg⁸]-vasopressin at EC₅₀concentration is added. The resulting light signal is measuredimmediately in a luminometer.

Vasopressin V2 Receptor Cell Lines:

On the day before the assay, the cells are plated out in culture medium(DMEM/F12, 2% FCS, 2 mM glutamine, 10 mM HEPES) in 384-well microtiterplates and kept in a cell incubator (96% humidity, 5% v/v CO₂, 37° C.).On the day of the assay, test compounds in various concentrations andthe agonist [Arg⁸]-vasopressin at EC₅₀ concentration are added togetherto the wells, and plates are incubated for 3 hours in a cell incubator.Upon addition of the cell lysis reagent Triton™ and the substrateluciferin, luminescence of firefly luciferase is measured in aluminometer.

Table 1A below lists individual IC₅₀ values for the compounds of theinvention (including racemic mixtures as well as separated enantiomers)that were obtained from cell lines transfected with the human Via or V2receptor:

TABLE 1A Example IC₅₀ hV1a IC₅₀ hV2 ratio IC₅₀ No. [μM] [μM] hV2/hV1a 10.00490 0.24500 50.0 2 0.04050 2.40000 59.3 3 0.00410 0.44500 108.5 40.05550 1.85000 33.3 5 0.01055 0.59500 56.4 6 0.00565 0.63000 111.5 70.00165 0.13000 78.8 8 0.04250 2.20000 51.8 9 0.01000 0.66000 66.0 100.00610 0.36500 59.8 11 0.00120 0.04550 37.9 12 0.02250 0.56000 24.9 130.00695 0.26000 37.4 14 0.01240 0.22000 17.7 15 0.00205 0.07850 38.3 160.00505 0.14000 27.7 17 0.00955 0.28000 29.3 18 0.00250 0.03350 13.4 190.00220 0.10150 46.1 20 0.00890 0.52000 58.4 21 0.00595 0.28250 47.5 220.00405 0.15000 37.0 23 0.00101 0.07250 71.8 24 0.00440 0.70750 160.8 250.00175 0.17250 98.6 26 0.00915 0.08250 9.0 27 0.21500 1.90000 8.8 280.00185 0.02250 12.2 29 0.00565 0.20333 36.0 30 0.00630 0.21333 33.9 310.00340 0.10900 32.1 32 0.00117 0.07825 67.0 33 0.21500 5.60000 26.1 340.00082 0.03350 40.9 36 0.00350 0.89000 254.3 37 0.29500 32.00000 108.538 0.00170 0.04800 28.2 39 0.00048 0.05325 110.9 40 0.37000 9.87500 26.741 0.00150 0.05700 38.0 42 1.35000 12.15000 9.0 43 0.00140 0.05725 40.944 0.00175 0.12000 68.6 45 0.23500 2.30000 9.8 46 0.00135 0.05775 42.847 0.00185 0.05000 27.0 48 0.00540 0.30500 56.5 49 0.00335 0.37750 112.750 0.00320 0.15000 46.9 51 0.00290 0.16700 57.6 52 0.00280 0.47000 167.953 0.00160 0.03800 23.8 54 0.00390 0.16500 42.3 55 0.00195 0.10600 54.456 0.00810 1.02667 126.8 57 0.03150 1.97667 62.8 58 0.00300 0.12050 40.259 0.00190 0.07500 39.5 60 0.01850 1.55000 83.8 61 0.05000 3.80000 76.062 0.00160 0.16500 103.1 63 0.00072 0.05875 82.2 64 0.00120 0.07825 65.265 0.00910 0.49000 53.8 66 0.00540 0.24500 45.4 67 0.00115 0.05700 49.668 0.00615 0.53000 86.2 69 0.00195 0.10100 51.8 70 0.00635 0.44500 70.171 0.00490 0.27500 56.1

B-2. Radioactive Binding Assay

IC₅₀ and K_(i) values can be determined in radioactive binding assaysusing membrane fractions of recombinant human embryonic kidney cell line293 (HEK293) or CHO-K1 cell lines expressing the respective humanvasopressin Via and V2 receptors.

Human recombinant vasopressin V1a receptors expressed in HEK293 cellsare used in 50 mM Tris-HCl buffer, pH 7.4, 5 mM MgCl₂, 0.1% BSA usingstandard techniques. Aliquots of prepared membranes are incubated withtest compounds in various concentrations in duplicates and 0.03 nM[¹²⁵I]Phenylacetyl-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH₂ for 120minutes at 25° C. Non-specific binding is estimated in the presence of 1μM [Arg⁸]Vasopressin. Receptors are filtered and washed, the filters arethen counted to determine[¹²⁵I]Phenylacetyl-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH₂specifically bound.

CHO-K1 cells stably transfected with a plasmid encoding humanvasopressin V2 receptor are used to prepare membranes in 50 mM Tris-HClbuffer, pH 7.4, 10 mM MgCl₂, 0.1% BSA using standard techniques.Aliquots of prepared membrane are incubated with test compounds invarious concentrations in duplicates and 4 nM [³H](Arg⁸)-Vasopressin for120 minutes at 25° C. Non-specific binding is estimated in the presenceof 1 mM (Arg⁸)-vasopressin. Membranes are filtered and washed 3 timesand the filters are counted to determine [³H](Arg₈)-Vasopressinspecifically bound.

IC₅₀ values are determined by a non-linear, least squares regressionanalysis using MathIQTM (ID Business Solutions Ltd., UK). The inhibitionconstant K_(i) is calculated using the equation of Cheng and Prusoff(Cheng, Y., Prusoff, W.H., Biochem. Pharmacol. 22:3099-3108, 1973).

B-3. Cellular In Vitro Assay for Detecting the Action of Vasopressin V1aReceptor Antagonists on the Regulation of Pro-Fibrotic Genes

The cell line H9C2 (American Type Culture Collection ATCC No. CRL-1446),described as a cardiomyocyte type isolated from rat cardiac tissue,endogenously expresses the vasopressin Via receptor AVPR1A in high copynumber, whereas AVPR2 expression cannot be detected. Likewise, the cellline NRK49F (ATCC No. CRL1570) isolated from rat kidney tissue, showssimilar expression pattern of high AVPR1A mRNA expression anddiminishing AVPR2 expression. For cell assays detecting the inhibitionof AVPR1A receptor-dependent regulation of gene expression by receptorantagonists, the procedure is as follows:

H9C2 cells or NRK49F cells are seeded in 6-well microtiter plates forcell culture at a cell density of 50 000 cells/well in 2.0 ml ofOpti-MEM medium (Invitrogen Corp., Carlsbad, Calif., USA, Cat. No.11058-021) and held in a cell incubator (96% humidity, 8% v/v CO₂, 37°C.). After 24 hours, sets of three wells (triplicate) are charged withvehicle solution (negative control) and vasopressin solution([Arg8]-vasopressin acetate, Sigma, Cat. No. V9879), or test compound(dissolved in vehicle: water with 20% v/v ethanol) and vasopressinsolution. In the cell culture, the final vasopressin concentration is 1nM. The test compound solution is added to the cell culture in smallvolumes, so that a final concentration of 0.03% of ethanol in the cellassay is not exceeded. After an incubation time of 5 hours, the culturesupernatant is drawn off under suction, the adherent cells are lysed in350 μl of RLT buffer (Qiagen, Cat. No. 79216), and the RNA is isolatedfrom the lysate using the RNeasy kit (Qiagen, Cat. No. 74104). This isfollowed by DNAse digestion (Invitrogen, Cat. No. 18068-015), cDNAsynthesis (Promaga, ImProm-II Reverse Transcription System, Cat. No.A3800) and Reverse Transcription Polymerase Chain Reaction (RTPCR) (pPCRMasterMix RT-QP2X-03-075, Eurogentec, Seraing, Belgium). All procedurestake place in accordance with the working protocols of the testreagents' manufacturers. The primer sets for the RTPCR are selected onthe basis of the mRNA gene sequences (NCBI GenBank Entrez NucleotideData Base) using the Primer3Plus program with 6-FAM TAMRA-labelledprobes. The RTPCR for determining the relative mRNA expression in thecells of the various assay batches is carried out using the AppliedBiosystems ABI Prism 7700 Sequence Detector in 384-well microtiter plateformat in accordance with the instrument operating instructions. Therelative gene expression is represented by the delta-delta Ct value[Applied Biosystems, User Bulletin No. 2 ABI Prism 7700 SDS, Dec. 11,1997 (updated 10/2001)] with reference to the level of expression of theribosomal protein L-32 gene (GenBank Acc. No. NM_013226) and thethreshold Ct value of Ct=35.

B-4. Inhibition of Vasopressin Induced Aggregation of Human Platelets

Human platelets endogenously express the V1a receptor. It was found thatrelatively high vasopressin concentrations (ca. 50-100 nM) stimulateplatelet aggregation ex vivo. Therefore, platelets enriched from humanblood may serve as a V1a expressing tissue for pharmacological studieswith corresponding high concentrations of vasopressin antagonists.

Human blood is collected in a 10 mM trisodium citrate solution by venouspuncture from nonsmoking healthy volunteers (n=4-8) who were drug freefor at least 1 week. Platelet-rich plasma (PRP) is obtained bycentrifuging the blood sample at 140 g for 20 min at 4° C. The resultingpellet is further centrifuged (15.000 rpm, 2 min) to produceplatelet-poor plasma (PPP). Platelet aggregation is measuredturbidimetrically using an aggregometer (APACT 4). The reaction isfollowed by monitoring changes in light transmission on 178 μL PRPaliquots, under continuous stirring at 37° C., against PPP control.Various concentrations of vasopressin antagonists (in 2 μL) are added toPRP 5 min before the addition of 20 μL Arg-vasopressin (finalconcentration 100 nM. The inhibitory effects of the compounds aredetermined by measuring the height of the aggregation wave from thebottom of the shape change compared with the control response. IC50values are calculated a dose-response inhibition curve by an iterativenonlinear regression program

B-5. Effects on the Contraction of Isolated Rat Vessel Rings

Isolated Aorta

Test compounds can be investigated on isolated aortic rings from maleWistar rats endogenously expressing the V1a receptor. Male Wistar ratsare euthanized using carbon dioxide. The aorta is removed and placed inice-cold Krebs-Henseleit buffer of following composition (in mmol/1):NaCl 112, KCl 5.9, CaCl₂ 2.0, MgCl₂ 1.2, NaH₂PO₄ 1.2, NaHCO₃ 25, glucose11.5. The aorta is cut into 3 mm rings and transferred to 20 ml organbaths containing Krebs-Henseleit solution equilibrated with 95% O₂, 5%CO₂ at 37° C. For recording of isometric tension the rings are mountedbetween two hooks. The resting tension is adjusted to 3 g. After anequilibration period, each experiment is started by exposing thepreparation to K+ (50 mM) Krebs-Henseleit solution. The aortic rings arethan pre-contracted using 1 nmol/l Arg-vasopressin. After a stablecontraction is established, a cumulative dose response curve of the testcompound is constructed. The stabilized contraction induced byArg-vasopressin is defined as 100% tension. The relaxation is expressedas percentage tension.

Isolated A. renalis

Male Wistar rats (200-250 g) are euthanized using carbon dioxide. The A.renalis is removed and placed in ice-cold Krebs-Henseleit buffer offollowing composition (in mmol/1): NaCl 112, KCl 5.9, CaCl₂ 2.0, MgCl₂1.2, NaH₂PO₄ 1.2, NaHCO₃ 25, glucose 11.5. For measurement of isometrictension, ring segments, 2 mm in length, are mounted in a small vesselchamber myograph (Danish Myo Technology A/S, Denmark) using two tungstenwires fixed to mounting jaws. One mounting jaw is attached to amicrometer, allowing control of vessel circumference. The other mountingjaw is attached to a force transducer for measurement of tensiondevelopment. The whole preparation is kept in a chamber withphysiological salt solution at 37° C., bubbled with oxygen. After a 30min equilibration period, the vessels are stretched to their optimallumen diameter for active tension development which is determined basedon the internal circumference-wall tension ratio. The internalcircumference is set to 90% of what the vessels would have if they areexposed to a passive tension equivalent to that produced by a transmuralpressure of 100 mmHg.

Afterwards, the vessels are washed three times with Krebs-Henseleitbuffer and left to equilibrate for 30 min. The contractility is thentested by a twofold exposure to a high K⁺ solution (50 mmol/l KCl).After washing with Krebs-Henseleit buffer the vessels are thenpre-contracted using 1 nmol/l Arg-vasopressin. After a stablecontraction is established, a cumulative dose response curve of the testcompound is constructed. The stabilized contraction induced byArg-vasopressin is defined as 100% tension. The relaxation is expressedas percentage tension.

B-6. In Vivo Assay for Detecting Cardiovascular Effects: Blood PressureMeasurement in Anaesthetized Rats (Vasopressin ‘Challenge’ Model)

Male Sprague-Dawley rats (250-350 g body weight) are used underketamine/xylazine/pentobarbital injection anaesthesia. Polyethylenetubes (PE-50, Intramedic®), prefilled with heparin-containing (500IU/ml) isotonic sodium chloride solution, are introduced into thejugular vein and the femoral vein and then tied in. Arg-vasopressin(SIGMA) is injected via one venous access, with the aid of a syringe;the test substance is administered via the second venous access. Fordetermination of the systolic blood pressure, a pressure catheter(Millar SPR-320 2F) is tied into the carotid artery. The arterialcatheter is connected to a pressure transducer which feeds its signalsto a recording computer equipped with suitable recording software. In atypical experiment, the experimental animal is administered 3-4successive bolus injections at intervals of 10-15 min with a definedamount of Arg-vasopressin (30 ng/kg) in isotonic sodium chloridesolution. When the blood pressure has reached initial levels again, thetest substance is administered as a bolus, with subsequent continuousinfusion, in a suitable solvent. After this, at defined intervals (10-15min), the same amount of Arg-vasopressin as at the start is administeredagain. On the basis of the blood pressure values, a determination ismade of the extent to which the test substance counteracts thehypertensive effect of Arg-vasopressin. Control animals only receivesolvent instead of the test substance.

Following intravenous administration, the compounds of the invention, incomparison to the solvent controls, bring about an inhibition of theblood pressure increase caused by Arg-vasopressin.

B-7. In Vivo Assay for Detecting Cardiovascular Effects: DiuresisInvestigations in Conscious Rats Kept in Metabolism Cages

Wistar rats (220-450 g body weight) are kept with free access to feed(Altromin) and drinking water. During the experiment, the animals arekept with free access to drinking water for 4 to 8 or up to 24 hoursindividually in metabolism cages suitable for rats of this weight class(Tecniplast Deutschland GmbH, D-82383 HohenpeilBenberg). At thebeginning of the experiment, the animals are administered the testsubstance in a volume of 1 to 3 ml/kg body weight of a suitable solventby means of gavage into the stomach. Control animals only receivesolvent. Controls and substance tests are carried out in parallel on thesame day. Control groups and substance-dose groups each consist of 4 to8 animals. During the experiment, the urine excreted by the animals iscollected continuously in a receiver at the base of the cage. The volumeof urine per time unit is determined separately for each animal, and theconcentration of urinary electrolytes is measured by standard methods offlame photometry. Before the beginning of the experiment, the bodyweight of the individual animals is determined.

B-8. In Vivo Assay for Detecting Protective Renal Effects: AcuteIschemia/Reperfusion Injury Model in Rodents

Laboratory bred male C57B1/6J mice 6-8 weeks old are obtained fromTaconic Biosciences, male 6-8 weeks old Sprague Dawley® rat are obtainedfrom Charles River. Both rats and mice are maintained under standardlaboratory conditions, 12 hour light-dark cycles with access to normalchow and drinking water at libitum. For the ischemia reperfusion injurymodel a total of 10-12 rats or mice is used in each control andexperimental group.

Animals are anesthetized with continuous inhaled isoflurane. A rightnephrectomy is performed through a right flank incision 7 days beforethe ischemic procedures in the contralateral kidneys.

For renal ischemia a left flank incision is made. Renal vessels areexposed by dissection of the left renal pedicle. Non-traumatic vascularclamps are used to stop blood flow (artery and vein) during 45 min(rats) or 25 min (mice) of ischemia. Reperfusion is established byremoving the clamps. The abdominal wall (muscular layer and skin) isclosed with 5.0 polypropylene sutures. Temgesic® (Buprenorphin, 0.025mg/kg s.c.) is applied as an analgesic.

Urine of each animal is collected in metabolic cages over night beforesacrifice at 24 h post ischemia. Upon sacrifice, blood samples areobtained under terminal anesthesia. After centrifugation of the bloodsamples, serum is isolated. Both serum creatinine and serum urea aremeasured via clinical biochemistry analyzer (Pentra 400). For theassessment of serum and urinary kidney injury biomarkers (Neutrophilgelatinase-associated lipocalin [NGAL], kidney injury molecule-1 [KIM-1]and Osteopontin) ELISA's are performed according to the manufacturersprotocol. Both urinary creatinine and albumin are measured to determinethe albumin/creatinine ratio.

Total RNA is isolated from kidneys. Left kidneys are snap-frozen inliquid nitrogen at sacrifice. Kidney tissue is then homogenized and RNAis obtained. Total RNA is transcribed to cDNA. Using TaqMan real-timePCR renal NGAL, Osteopontin, KIM-1, Nephrin and Podocin mRNA expressionis analyzed in whole kidney tissue.

Differences between groups are analyzed by one-way ANOVA with Dunnett'scorrections for multiple comparisons. Statistical significance isdefined as p<0.05. All statistical analyses are done using GraphPadPrism 6.

B-9. In Vivo Assay for Detecting Cardiovascular Effects: HemodynamicInvestigations in Anesthetized Dogs

Male beagle dogs (Beagle, Marshall BioResources, USA) with a weight ofbetween 10 and 15 kg are anesthetized with pentobarbital (30 mg/kg iv,Narcoren®, Merial, Germany) for the surgical interventions and thehemodynamic and functional investigation termini. Pancuroniumbromide(Pancuronium Inresa, Inresa, Germany, 2-4 mg/animal i.v.) servesadditionally as a muscle relaxant. The dogs are intubated and ventilatedwith an oxygen/ambient air mixture (30/70%), about 2,5-4 L/min.Ventilation takes place using a ventilator from GE Healthcare (Avance,Germany) and is monitored using a carbon dioxide analyzer (-DatexOhmeda). The anesthesia is maintained by continual infusion ofpentobarbital (50 μg/kg/min); fentanyl is used as an analgesic (10μg/kg/h).

In preparatory interventions, the dogs are fitted with a cardiacpacemaker. At start of experiment, a cardiac pacemaker from Biotronik(Logos®, Germany) is implanted into a subcutaneous skin pocket and iscontacted with the heart via a pacemaker electrode (Siello S60®,Biotronik, Germany) which is advanced through the external jugular vein,with illumination, into the right ventricle.

Thereafter accesses are removed and the dog wakes spontaneously from theanesthesia. After a further 7 days, the above-described pacemaker isactivated and the heart is stimulated at a frequency of 220 beats perminute.

The actual drug testing experiments take place 28 days after thebeginning of pacemaker stimulation, using the following instrumentation:

-   -   Introduction of a bladder catheter for bladder relief and for        measuring the flow of urine    -   Attachment of electrocardiography (ECG) leads to the extremities        for ECG measurement    -   Introduction of a sheath introducer filled with sodium chloride        solution into the femoral artery. This tube is connected to a        pressure sensor (Braun Melsungen, Melsungen, Germany) for        measuring the systemic blood pressure    -   Introduction of a Millar Tip catheter (type 350 PC, Millar        Instruments, Houston, USA) through a port secured in the carotid        artery, for measuring cardiac hemodynamics.    -   Introduction of a Swan-Ganz catheter (CCOmbo 7.5F, Edwards,        Irvine, USA) via the jugular vein into the pulmonary artery, for        measuring the cardiac output, oxygen saturation, pulmonary        arterial pressures and central venous pressure    -   Siting of a venous catheter in the cephalic vein, for infusing        pentobarbital, for liquid replacement and for blood sampling        (determination of the plasma levels of substance or other        clinical blood values)    -   Siting of a venous catheter in the saphenous vein, for infusing        fentanyl and for administration of substance    -   Infusion of vasopressin (Sigma) in increasing dosage, up to a        dose of 4 mU/kg/min. The pharmacological substances are then        tested with this dosage.

The primary signals are amplified if necessary (ACQ7700, Data SciencesInternational, USA or Edwards-Vigilance-Monitor, Edwards, Irvine, USA)and subsequently fed into the Ponemah system (Data SciencesInternational, USA) for evaluation. The signals are recordedcontinuously throughout the experimental period, and are furtherprocessed digitally by said software, and averaged over 30 seconds.

Although the invention has been disclosed with reference to specificembodiments, it is apparent that other embodiments and variations of theinvention may be devised by others skilled in the art without departingfrom the true spirit and scope of the invention. The claims are intendedto be construed to include all such embodiments and equivalentvariations.

C) Working Examples of Pharmaceutical Compositions

The substances according to the invention can be converted topharmaceutical preparations as follows:

Tablet:

Composition:

100 mg of the compound of Example 1, 50 mg of lactose (monohydrate), 50mg of maize starch, 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF,Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

Production: The mixture of the compound of Example 1, lactose and starchis granulated with a 5% strength solution (m/m) of the PVP in water.After drying, the granules are mixed with the magnesium stearate for 5min. This mixture is compressed in a conventional tabletting press (seeabove for format of the tablet).

Oral Suspension:

Composition:

1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mgof Rhodigel (xanthan gum) (from FMC, USA) and 99 g of water.

10 ml of oral suspension correspond to a single dose of 100 mg of thecompound of the invention.

Production:

The Rhodigel is suspended in ethanol, and the compound of Example 1 isadded to the suspension. The water is added while stirring. The mixtureis stirred for about 6 h until swelling of the Rhodigel is complete.

Sterile i.v. Solution:

The compound according to the invention is dissolved at a concentrationbelow saturation solubility in a physiologically acceptable solvent (forexample isotonic sodium chloride solution, glucose solution 5% and/orPEG 400 solution 30%). The solution is sterilized by filtration andfilled into sterile and pyrogen-free injection containers.

The invention claimed is:
 1. A compound of formula (I)

in which R¹ represents C₁-C₄-alkyl, 3,3,3-trifluoro-prop-1-en-1-yl,2,3,3-trifluoro-prop-2-en-1-yl, cyclopropyl, cyclobutyl, oxetan-2-yl,oxetan-3-yl, azetidin-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,1,1-dioxo-thietan-3-yl, 1,1-dioxo-tetrahydrothiophen-3-yl,5-chloro-thiophen-2-yl or 2-oxoimidazolidin-4-yl, where alkyl may besubstituted by 1 or 2 substituents independently of one another selectedfrom the group consisting of cyano, fluorine, hydroxy, trifluoromethyl,methoxy, methylsulfonyl, methylcarbonyloxy, methylsulfonylamino and2-oxo-1,3-oxazolidin-3-yl, and where cyclopropyl and cyclobutyl may besubstituted by 1 or 2 substituents independently of one another selectedfrom the group consisting of cyano, fluorine, hydroxy, amino,trifluoromethyl and tert-butoxycarbonylamino, and where azetidin-2-ylmay be substituted by 1 to 3 substituents independently of one anotherselected from the group consisting of fluorine and tert-butoxycarbonyl,and where pyrrolidin-2-yl and pyrrolidin-3-yl may be substituted by 1 or2 substituents independently of one another selected from the groupconsisting of oxo, fluorine, trifluoromethyl and tert-butoxycarbonyl, R²represents chlorine, trifluoromethyl or trifluoromethoxy, And/or apharmaceutically acceptable salt thereof, solvate thereof and/or solvateof a salt thereof.
 2. A compound of according to claim 1, wherein R¹represents methyl, ethyl, 3,3,3-trifluoro-prop-1-en-1-yl,1-trifluoromethylcycloprop-1-yl, 2,2-difluorocycloprop-1-yl,4-fluoropyrrolidin-2-yl, 5-oxopyrrolidin-2-yl, 1,1-dioxo-thietan-3-yl or5-chloro-thiophen-2-yl, where methyl is substituted by one substituentselected from the group consisting of trifluoromethyl, methoxy andmethylsulfonyl, and where ethyl is substituted by one substituenttrifluoromethyl, R² represents chlorine or trifluoromethyl, And/or apharmaceutically acceptable salt thereof, solvate thereof and/or solvateof a salt thereof.
 3. A compound of according to claim 1, wherein R¹represents methyl, ethyl, 2,2-difluorocycloprop-1-yl,4-fluoropyrrolidin-2-yl or 5-oxopyrrolidin-2-yl, where methyl issubstituted by one substituent methylsulfonyl, and where ethyl issubstituted by one substituent trifluoromethyl, R² represents chlorine,And/or a pharmaceutically acceptable salt thereof, solvate thereofand/or solvate of a salt thereof.
 4. Process for preparing a compound ofthe formula (I) and/or a pharmaceutically acceptable salt thereof,solvate thereof and/or solvate of a salt thereof according to claim 1,comprising reacting a compound of formula II

with a compound of formula III

in which X¹ represents chlorine or hydroxy, and to give a compound offormula (I), optionally followed, where appropriate, by (I) separatingthe compound of the formula (I) thus obtained into a respectivediastereomer, and/or (ii) converting the compound of the formula (I)into a respective pharmaceutically acceptable salt thereof, solvatethereof or a solvate of a salt thereof by treatment with a correspondingsolvent and/or acid or base.
 5. Compound as defined in claim 1 fortreatment and/or prevention of one or more diseases.
 6. Compound asdefined in claim 1 for treatment and/or prevention of one or more acuteand chronic kidney diseases optionally including one or more of diabeticnephropathy, acute and chronic heart failure, preeclampsia, peripheralarterial disease (PAD), coronary microvascular dysfunction (CMD),Raynaud's syndrome, dysmenorrhea, cardiorenal syndrome, hypervolemic andeuvolemic hyponatremia, liver cirrhosis, ascites, edema and the syndromeof inadequate ADH secretion (SIADH).
 7. A product comprising a compoundas defined in claim 1 for manufacture of a pharmaceutical compositionfor treatment and/or prevention of one or more acute and chronic kidneydiseases optionally including one or more of diabetic nephropathy, acuteand chronic heart failure, preeclampsia, peripheral arterial disease(PAD), coronary microvascular dysfunction (CMD), Raynaud's syndromedysmenorrhea, cardiorenal syndrome, hypervolemic and euvolemichyponatremia, liver cirrhosis, ascites, edema and the syndrome ofinadequate ADH secretion (SIADH).
 8. Pharmaceutical compositioncomprising a compound as defined in claim 1 and one or morepharmaceutically acceptable excipients.
 9. Pharmaceutical composition ofclaim 8 comprising one or more first active ingredients, optionally oneor more compounds of according to claim 1, and one or more furtheractive ingredients, optionally one or more additional therapeutic agentsselected from the group consisting of diuretics, angiotensin Allantagonists, ACE inhibitors, beta-receptor blockers, mineralocorticoidreceptor antagonists, organic nitrates, NO donors, activators andstimulators of the soluble guanylate cyclase, and positive-inotropicagents, antiinflammatory agents, immunosuppressive agents, phosphatebinders and/or compounds which modulate vitamin D metabolism.
 10. Thepharmaceutical composition as defined in claim 8 for treatment and/orprevention of one or more acute and chronic kidney diseases optionallyincluding one or more of diabetic nephropathy, acute and chronic heartfailure, preeclampsia, peripheral arterial disease (PAD), coronarymicrovascular dysfunction (CMD), Raynaud's syndrome, dysmenorrhea,cardiorenal syndrome, hypervolemic and euvolemic hyponatremia, livercirrhosis, ascites, edema and the syndrome of inadequate ADH secretion(SIADH).
 11. Method for treatment and/or prevention of acute and chronickidney diseases optionally including one or more of diabeticnephropathy, acute and chronic heart failure, preeclampsia, peripheralarterial disease (PAD) and coronary microvascular dysfunction (CMD),Raynaud's syndrome dysmenorrhea, cardiorenal syndrome, hypervolemic andeuvolemic hyponatremia, liver cirrhosis, ascites, edema and the syndromeof inadequate ADH secretion (SIADH) in a human or other mammal, saidmethod comprising administering to a human or other mammal in needthereof, a therapeutically effective amount of one or more compounds asdefined in claim 1, or a pharmaceutical composition thereof.